Pathobiology of Pulmonary Arterial Hypertension

Michael      Lewis; Norbert      Voelkel; Ferdous      Kadri
doi:10.2174/011573398X266579240226064718
Abstract

Pulmonary Arterial Hypertension (PAH) is a progressive disease associated with occlusive pulmonary arterial remodeling of vessels < 500 μm for which there is no cure. Even in the era of PAH-specific combination therapies, aberrant lung pathology and progressive right ventricular (RV) dysfunction occur, culminating in a median survival of 6.2 years, according to the latest data in the treatment era. While better than a median survival from symptom onset of 2.8 years prior to PAH-specific therapies, it is still poor. Thus, there is an urgent need to move the opportunities forward for meaningful treatment strategies. Clearly, a better understanding of the highly complex pathobiology of PAH is needed if we are to achieve new and novel treatment strategies. This is especially so if we are to pursue a more personalized treatment approach to PAH in light of the multitude of pathobiological abnormalities described in PAH, which likely culminate in a final common pathway for PAH development.
In this State-of-the-Art review, we provide comprehensive insights into the complex pathobiology of PAH to provide understanding and insights for the practicing clinician. We review the pathology of PAH and the cells involved and their impact in driving pathological abnormalities (pulmonary artery endothelial cells, smooth muscle cells, fibroblasts and pericytes) as well as the role of the extracellular matrix. Inflammation and immune dysfunction are considered important drivers of PAH and are comprehensively discussed. Another pathway relates to TGFβ/ bone morphogenic protein (BMP) imbalance, which is highlighted, as well as a new novel agent, sotatercept that impacts this imbalance. Genetic factors underlying heritable PAH (HPAH) are addressed, as well as epigenetic influences. Other important pathways highlighted include growth factor signaling, ion channels/channelopathy, hypoxia signaling pathways, and altered metabolism and mitochondrial dysfunction. We also address the “estrogen paradox”, whereby PAH is more common in women but more severe in men. The basis for drug-induced PAH is discussed, including the new methamphetamine epidemic. We briefly provide insights into DNA damage and senescence factors in pathobiology and highlight commonalities between PAH and cancer pathobiology. Furthermore, we provide concluding insights for the treating physician. In conclusion, we need to pose the right questions to motivate novel and effective treatment strategies for the management of PAH based on pathobiological principles and understanding.
Keywords: Pulmonary artery endothelial cells, pulmonary artery smooth muscle cells, intimal hyperplasia, medial hypertrophy, plexiform lesions, inflammation, immune dysfunction, TGFβ, BMP, mutations, growth factors, channelopathy, Warburg phenomenon, mitochondrial dysfunction, hypoxia, estrogen paradox, DNA damage, senescence, drug-induced PAH, cancer hypothesis.
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Graphical Abstract

[1]
Hassoun, P.M. Pulmonary arterial hypertension. N. Engl. J. Med.,  2021, 385(25), 2361-2376.
 [http://dx.doi.org/10.1056/NEJMra2000348] [PMID: 34910865]

[2]
D’Alonzo, G.E.; Barst, R.J.; Ayres, S.M.; Bergofsky, E.H.; Brundage, B.H.; Detre, K.M.; Fishman, A.P.; Goldring, R.M.; Groves, B.M.; Kernis, J.T.; Levy, P.S.; Pietra, G.G.; Reid, L.M.; Reeves, J.T.; Rich, S.; Vreim, C.E.; Williams, G.W.; Wu, M. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann. Intern. Med.,  1991, 115(5), 343-349.
 [http://dx.doi.org/10.7326/0003-4819-115-5-343] [PMID: 1863023]

[3]
Hendriks, P.M.; Staal, D.P.; van de Groep, L.D.; van den Toorn, L.M.; Chandoesing, P.P.; Kauling, R.M.; Mager, H.J.; van den Bosch, A.E.; Post, M.C.; Boomars, K.A. The evolution of survival of pulmonary arterial hypertension over 15 years. Pulm. Circ.,  2022, 12(4), e12137.
 [http://dx.doi.org/10.1002/pul2.12137] [PMID: 36268054]

[4]
Heath, D.; Edwards, J. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation,  1958, 18(4), 533-547.
 [http://dx.doi.org/10.1161/01.CIR.18.4.533] [PMID: 13573570]

[5]
Rabinovitch, M.; Haworth, S.G.; Vance, Z.; Vawter, G.; Castaneda, A.R.; Nadas, A.S.; Reid, L.M. Early pulmonary vascular changes in congenital heart disease studied in biopsy tissue. Hum. Pathol.,  1980, 11(S5), 499-509.
 [PMID: 7429501]

[6]
Wagenvoort, C.A. The pathology of primary pulmonary hypertension. J Pathol,  1970, 101(4)

[7]
Pietra, G.G.; Edwards, W.D.; Kay, J.M.; Rich, S.; Kernis, J.; Schloo, B.; Ayres, S.M.; Bergofsky, E.H.; Brundage, B.H.; Detre, K.M. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation,  1989, 80(5), 1198-1206.
 [http://dx.doi.org/10.1161/01.CIR.80.5.1198] [PMID: 2805258]

[8]
Pietra, G.G.; Capron, F.; Stewart, S.; Leone, O.; Humbert, M.; Robbins, I.M.; Reid, L.M.; Tuder, R.M. Pathologic assessment of vasculopathies in pulmonary hypertension. J. Am. Coll. Cardiol.,  2004, 43(12), S25-S32.
 [http://dx.doi.org/10.1016/j.jacc.2004.02.033] [PMID: 15194175]

[9]
Stacher, E.; Graham, B.B.; Hunt, J.M.; Gandjeva, A.; Groshong, S.D.; McLaughlin, V.V.; Jessup, M.; Grizzle, W.E.; Aldred, M.A.; Cool, C.D.; Tuder, R.M. Modern age pathology of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2012, 186(3), 261-272.
 [http://dx.doi.org/10.1164/rccm.201201-0164OC] [PMID: 22679007]

[10]
Pogoriler, J.E.; Rich, S.; Archer, S.L.; Husain, A.N. Persistence of complex vascular lesions despite prolonged prostacyclin therapy of pulmonary arterial hypertension. Histopathology,  2012, 61(4), 597-609.
 [http://dx.doi.org/10.1111/j.1365-2559.2012.04246.x] [PMID: 22748137]

[11]
Dorfmüller, P.; Humbert, M.; Capron, F.; Müller, K.M. Pathology and aspects of pathogenesis in pulmonary arterial hypertension. Sarcoidosis Vasc. Diffuse Lung Dis.,  2003, 20(1), 9-19.
 [PMID: 12737275]

[12]
Humbert, M.; Guignabert, C.; Bonnet, S.; Dorfmüller, P.; Klinger, J.R.; Nicolls, M.R.; Olschewski, A.J.; Pullamsetti, S.S.; Schermuly, R.T.; Stenmark, K.R.; Rabinovitch, M. Pathology and pathobiology of pulmonary hypertension: State of the art and research perspectives. Eur. Respir. J.,  2019, 53(1), 1801887.
 [http://dx.doi.org/10.1183/13993003.01887-2018] [PMID: 30545970]

[13]
Trip, P.; Nossent, E.J.; de Man, F.S.; van den Berk, I.A.H.; Boonstra, A.; Groepenhoff, H.; Leter, E.M.; Westerhof, N.; Grünberg, K.; Bogaard, H.J.; Noordegraaf, V.A. Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: Patient characteristics and treatment responses. Eur. Respir. J.,  2013, 42(6), 1575-1585.
 [http://dx.doi.org/10.1183/09031936.00184412] [PMID: 23949959]

[14]
Montani, D.; Lau, E.M.; Dorfmüller, P.; Girerd, B.; Jaïs, X.; Savale, L.; Perros, F.; Nossent, E.; Garcia, G.; Parent, F.; Fadel, E.; Soubrier, F.; Sitbon, O.; Simonneau, G.; Humbert, M. Pulmonary veno-occlusive disease. Eur. Respir. J.,  2016, 47(5), 1518-1534.
 [http://dx.doi.org/10.1183/13993003.00026-2016] [PMID: 27009171]

[15]
Cober, N.D.; VandenBroek, M.M.; Ormiston, M.L.; Stewart, D.J. Evolving concepts in endothelial pathobiology of pulmonary arterial hypertension. Hypertension,  2022, 79(8), 1580-1590.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.122.18261] [PMID: 35582968]

[16]
Budhiraja, R.; Tuder, R.M.; Hassoun, P.M. Endothelial dysfunction in pulmonary hypertension. Circulation,  2004, 109(2), 159-165.
 [http://dx.doi.org/10.1161/01.CIR.0000102381.57477.50] [PMID: 14734504]

[17]
Sakao, S.; Taraseviciene-Stewart, L.; Lee, J.D.; Wood, K.; Cool, C.D.; Voelkel, N.F. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. FASEB J.,  2005, 19(9), 1178-1180.
 [http://dx.doi.org/10.1096/fj.04-3261fje] [PMID: 15897232]

[18]
Kuliszewska, T.K.; Kutryk, M.J.B.; Kuliszewski, M.A.; Karoubi, G.; Courtman, D.W.; Zucco, L.; Granton, J.; Stewart, D.J. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: Implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ. Res.,  2006, 98(2), 209-217.
 [http://dx.doi.org/10.1161/01.RES.0000200180.01710.e6] [PMID: 16357305]

[19]
Hemnes, A.R.; Humbert, M. Pathobiology of pulmonary arterial hypertension: Understanding the roads less travelled. Eur. Respir. Rev.,  2017, 26(146), 170093.
 [http://dx.doi.org/10.1183/16000617.0093-2017] [PMID: 29263173]

[20]
Stenmark, K.R.; Frid, M.; Perros, F. Endothelial-to-mesenchymal transition. Circulation,  2016, 133(18), 1734-1737.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022479] [PMID: 27045137]

[21]
Hopper, R.K.; Moonen, J.R.A.J.; Diebold, I.; Cao, A.; Rhodes, C.J.; Tojais, N.F.; Hennigs, J.K.; Gu, M.; Wang, L.; Rabinovitch, M. In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to-mesenchymal transition via HMGA1 and its target slug. Circulation,  2016, 133(18), 1783-1794.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020617] [PMID: 27045138]

[22]
Chien, S. Effects of disturbed flow on endothelial cells. Ann. Biomed. Eng.,  2008, 36(4), 554-562.
 [http://dx.doi.org/10.1007/s10439-007-9426-3] [PMID: 18172767]

[23]
Ranchoux, B.; Antigny, F.; Rucker-Martin, C.; Hautefort, A.; Péchoux, C.; Bogaard, H.J.; Dorfmüller, P.; Remy, S.; Lecerf, F.; Planté, S.; Chat, S.; Fadel, E.; Houssaini, A.; Anegon, I.; Adnot, S.; Simonneau, G.; Humbert, M.; Kaminsky, C.S.; Perros, F. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation,  2015, 131(11), 1006-1018.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.114.008750] [PMID: 25593290]

[24]
Lechartier, B.; Berrebeh, N.; Huertas, A.; Humbert, M.; Guignabert, C.; Tu, L. Phenotypic diversity of vascular smooth muscle cells in pulmonary arterial hypertension. Chest,  2022, 161(1), 219-231.
 [http://dx.doi.org/10.1016/j.chest.2021.08.040] [PMID: 34391758]

[25]
Cool, C.D.; Kuebler, W.M.; Bogaard, H.J.; Spiekerkoetter, E.; Nicolls, M.R.; Voelkel, N.F. The hallmarks of severe pulmonary arterial hypertension: The cancer hypothesis—ten years later. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2020, 318(6), L1115-L1130.
 [http://dx.doi.org/10.1152/ajplung.00476.2019] [PMID: 32023082]

[26]
Ntokou, A.; Dave, J.M.; Kauffman, A.C.; Sauler, M.; Ryu, C.; Hwa, J.; Herzog, E.L.; Singh, I.; Saltzman, W.M.; Greif, D.M. Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension. JCI Insight,  2021, 6(6), e139067.
 [http://dx.doi.org/10.1172/jci.insight.139067] [PMID: 33591958]

[27]
Yu, Y.R.A.; Malakhau, Y.; Yu, C.H.A.; Phelan, S.L.J.; Cumming, R.I.; Kan, M.J.; Mao, L.; Rajagopal, S.; Piantadosi, C.A.; Gunn, M.D. Nonclassical monocytes sense hypoxia, regulate pulmonary vascular remodeling, and promote pulmonary hypertension. J. Immunol.,  2020, 204(6), 1474-1485.
 [http://dx.doi.org/10.4049/jimmunol.1900239] [PMID: 31996456]

[28]
Wang, D.; Zhang, H.; Li, M.; Frid, M.G.; Flockton, A.R.; McKeon, B.A.; Yeager, M.E.; Fini, M.A.; Morrell, N.W.; Pullamsetti, S.S.; Velegala, S.; Seeger, W.; McKinsey, T.A.; Sucharov, C.C.; Stenmark, K.R. MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ. Res.,  2014, 114(1), 67-78.
 [http://dx.doi.org/10.1161/CIRCRESAHA.114.301633] [PMID: 24122720]

[29]
Stenmark, K.R.; Frid, M.G.; Yeager, M.; Li, M.; Riddle, S.; McKinsey, T.; Kasmi, K.C.E. Targeting the adventitial microenvironment in pulmonary hypertension: A potential approach to therapy that considers epigenetic change. Pulm. Circ.,  2012, 2(1), 3-14.
 [http://dx.doi.org/10.4103/2045-8932.94817] [PMID: 22558514]

[30]
Qian, J.; Tian, W.; Jiang, X.; Tamosiuniene, R.; Sung, Y.K.; Shuffle, E.M.; Tu, A.B.; Valenzuela, A.; Jiang, S.; Zamanian, R.T.; Fiorentino, D.F.; Voelkel, N.F.; Golden, P.M.; Stenmark, K.R.; Chung, L.; Rabinovitch, M.; Nicolls, M.R. Leukotriene B 4 activates pulmonary artery adventitial fibroblasts in pulmonary hypertension. Hypertension,  2015, 66(6), 1227-1239.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06370] [PMID: 26558820]

[31]
Zhang, H.; Wang, D.; Li, M.; Hlavatá, P.L.; D’Alessandro, A.; Tauber, J.; Riddle, S.; Kumar, S.; Flockton, A.; McKeon, B.A.; Frid, M.G.; Reisz, J.A.; Caruso, P.; El Kasmi, K.C.; Ježek, P.; Morrell, N.W.; Hu, C.J.; Stenmark, K.R. Metabolic and proliferative state of vascular adventitial fibroblasts in pulmonary hypertension is regulated through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/pyruvate kinase muscle axis. Circulation,  2017, 136(25), 2468-2485.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028069] [PMID: 28972001]

[32]
El Kasmi, K.C.; Pugliese, S.C.; Riddle, S.R.; Poth, J.M.; Anderson, A.L.; Frid, M.G.; Li, M.; Pullamsetti, S.S.; Savai, R.; Nagel, M.A.; Fini, M.A.; Graham, B.B.; Tuder, R.M.; Friedman, J.E.; Eltzschig, H.K.; Sokol, R.J.; Stenmark, K.R. Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J. Immunol.,  2014, 193(2), 597-609.
 [http://dx.doi.org/10.4049/jimmunol.1303048] [PMID: 24928992]

[33]
Yuan, K.; Orcholski, M.E.; Panaroni, C.; Shuffle, E.M.; Huang, N.F.; Jiang, X.; Tian, W.; Vladar, E.K.; Wang, L.; Nicolls, M.R.; Wu, J.Y.; de Perez, J.V.A. Activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis. Am. J. Pathol.,  2015, 185(1), 69-84.
 [http://dx.doi.org/10.1016/j.ajpath.2014.09.013] [PMID: 25447046]

[34]
Ricard, N.; Tu, L.; Le Hiress, M.; Huertas, A.; Phan, C.; Thuillet, R.; Sattler, C.; Fadel, E.; Seferian, A.; Montani, D.; Dorfmüller, P.; Humbert, M.; Guignabert, C. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation,  2014, 129(15), 1586-1597.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.113.007469] [PMID: 24481949]

[35]
Thenappan, T.; Chan, S.Y.; Weir, E.K. Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension. Am. J. Physiol. Heart Circ. Physiol.,  2018, 315(5), H1322-H1331.
 [http://dx.doi.org/10.1152/ajpheart.00136.2018] [PMID: 30141981]

[36]
Hunter, K.S.; Lammers, S.R.; Shandas, R. Pulmonary vascular stiffness: Measurement, modeling, and implications in normal and hypertensive pulmonary circulations. Compr. Physiol.,  2011, 1(3), 1413-1435.
 [http://dx.doi.org/10.1002/cphy.c100005] [PMID: 23733649]

[37]
Hoffmann, J.; Marsh, L.M.; Pieper, M.; Stacher, E.; Ghanim, B.; Kovacs, G.; König, P.; Wilkens, H.; Haitchi, H.M.; Hoefler, G.; Klepetko, W.; Olschewski, H.; Olschewski, A.; Kwapiszewska, G. Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2015, 308(10), L1002-L1013.
 [http://dx.doi.org/10.1152/ajplung.00383.2014] [PMID: 25840998]

[38]
Todorovich-Hunter, L.; Dodo, H.; Ye, C.; McCready, L.; Keeley, F.W.; Rabinovitch, M. Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am. Rev. Respir. Dis.,  1992, 146(1), 213-223.
 [http://dx.doi.org/10.1164/ajrccm/146.1.213] [PMID: 1626806]

[39]
Jones, P.L.; Rabinovitch, M. Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ. Res.,  1996, 79(6), 1131-1142.
 [http://dx.doi.org/10.1161/01.RES.79.6.1131] [PMID: 8943951]

[40]
Chelladurai, P.; Seeger, W.; Pullamsetti, S.S. Matrix metalloproteinases and their inhibitors in pulmonary hypertension. Eur. Respir. J.,  2012, 40(3), 766-782.
 [http://dx.doi.org/10.1183/09031936.00209911] [PMID: 22523364]

[41]
Kim, Y.M.; Haghighat, L.; Spiekerkoetter, E.; Sawada, H.; Alvira, C.M.; Wang, L.; Acharya, S.; Colon, R.G.; Orton, A.; Zhao, M.; Rabinovitch, M. Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions. Am. J. Pathol.,  2011, 179(3), 1560-1572.
 [http://dx.doi.org/10.1016/j.ajpath.2011.05.051] [PMID: 21763677]

[42]
Bertero, T.; Cottrill, K.A.; Annis, S.; Bhat, B.; Gochuico, B.R.; Osorio, J.C.; Rosas, I.; Haley, K.J.; Corey, K.E.; Chung, R.T.; Nelson Chau, B.; Chan, S.Y. A YAP/TAZ-miR-130/301 molecular circuit exerts systems-level control of fibrosis in a network of human diseases and physiologic conditions. Sci. Rep.,  2015, 5(1), 18277.
 [http://dx.doi.org/10.1038/srep18277] [PMID: 26667495]

[43]
Bertero, T.; Oldham, W.M.; Cottrill, K.A.; Pisano, S.; Vanderpool, R.R.; Yu, Q.; Zhao, J.; Tai, Y.; Tang, Y.; Zhang, Y.Y.; Rehman, S.; Sugahara, M.; Qi, Z.; Gorcsan, J., III; Vargas, S.O.; Saggar, R.; Saggar, R.; Wallace, W.D.; Ross, D.J.; Haley, K.J.; Waxman, A.B.; Parikh, V.N.; De Marco, T.; Hsue, P.Y.; Morris, A.; Simon, M.A.; Norris, K.A.; Gaggioli, C.; Loscalzo, J.; Fessel, J.; Chan, S.Y. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J. Clin. Invest.,  2016, 126(9), 3313-3335.
 [http://dx.doi.org/10.1172/JCI86387] [PMID: 27548520]

[44]
Cohen-Kaminsky, S.; Hautefort, A.; Price, L.; Humbert, M.; Perros, F. Inflammation in pulmonary hypertension: What we know and what we could logically and safely target first. Drug Discov. Today,  2014, 19(8), 1251-1256.
 [http://dx.doi.org/10.1016/j.drudis.2014.04.007] [PMID: 24747559]

[45]
Hassoun, P.M.; Mouthon, L.; Barberà, J.A.; Eddahibi, S.; Flores, S.C.; Grimminger, F.; Jones, P.L.; Maitland, M.L.; Michelakis, E.D.; Morrell, N.W.; Newman, J.H.; Rabinovitch, M.; Schermuly, R.; Stenmark, K.R.; Voelkel, N.F.; Yuan, J.X.J.; Humbert, M. Inflammation, growth factors, and pulmonary vascular remodeling. J. Am. Coll. Cardiol.,  2009, 54(S1), S10-S19.
 [http://dx.doi.org/10.1016/j.jacc.2009.04.006] [PMID: 19555853]

[46]
Rabinovitch, M.; Guignabert, C.; Humbert, M.; Nicolls, M.R. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ. Res.,  2014, 115(1), 165-175.
 [http://dx.doi.org/10.1161/CIRCRESAHA.113.301141] [PMID: 24951765]

[47]
Tuder, R.M.; Archer, S.L.; Dorfmüller, P.; Erzurum, S.C.; Guignabert, C.; Michelakis, E.; Rabinovitch, M.; Schermuly, R.; Stenmark, K.R.; Morrell, N.W. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J. Am. Coll. Cardiol.,  2013, 62(S25), D4-D12.
 [http://dx.doi.org/10.1016/j.jacc.2013.10.025] [PMID: 24355640]

[48]
Tuder, R.M.; Voelkel, N.F. Pulmonary hypertension and inflammation. J. Lab. Clin. Med.,  1998, 132(1), 16-24.
 [http://dx.doi.org/10.1016/S0022-2143(98)90020-8] [PMID: 9665367]

[49]
Dorfmüller, P.; Humbert, M.; Perros, F.; Sanchez, O.; Simonneau, G.; Müller, K.M.; Capron, F. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum. Pathol.,  2007, 38(6), 893-902.
 [http://dx.doi.org/10.1016/j.humpath.2006.11.022] [PMID: 17376507]

[50]
Tuder, R.M.; Groves, B.; Badesch, D.B.; Voelkel, N.F. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am. J. Pathol.,  1994, 144(2), 275-285.
 [PMID: 7508683]

[51]
Guignabert, C.; Raffestin, B.; Benferhat, R.; Raoul, W.; Zadigue, P.; Rideau, D.; Hamon, M.; Adnot, S.; Eddahibi, S. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation,  2005, 111(21), 2812-2819.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.104.524926] [PMID: 15927991]

[52]
Stenmark, K.R.; Meyrick, B.; Galie, N.; Mooi, W.J.; McMurtry, I.F. Animal models of pulmonary arterial hypertension: The hope for etiological discovery and pharmacological cure. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2009, 297(6), L1013-L1032.
 [http://dx.doi.org/10.1152/ajplung.00217.2009] [PMID: 19748998]

[53]
Tamosiuniene, R.; Tian, W.; Dhillon, G.; Wang, L.; Sung, Y.K.; Gera, L.; Patterson, A.J.; Agrawal, R.; Rabinovitch, M.; Ambler, K.; Long, C.S.; Voelkel, N.F.; Nicolls, M.R. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ. Res.,  2011, 109(8), 867-879.
 [http://dx.doi.org/10.1161/CIRCRESAHA.110.236927] [PMID: 21868697]

[54]
Frid, M.G.; McKeon, B.A.; Thurman, J.M.; Maron, B.A.; Li, M.; Zhang, H.; Kumar, S.; Sullivan, T.; Laskowsky, J.; Fini, M.A.; Hu, S.; Tuder, R.M.; Gandjeva, A.; Wilkins, M.R.; Rhodes, C.J.; Ghataorhe, P.; Leopold, J.A.; Wang, R.S.; Holers, V.M.; Stenmark, K.R. Immunoglobulin-driven complement activation regulates proinflammatory remodeling in pulmonary hypertension. Am. J. Respir. Crit. Care Med.,  2020, 201(2), 224-239.
 [http://dx.doi.org/10.1164/rccm.201903-0591OC] [PMID: 31545648]

[55]
Schweitzer, F.; Tarantelli, R.; Rayens, E.; Kling, H.M.; Mattila, J.T.; Norris, K.A. Monocyte and alveolar macrophage skewing is associated with the development of pulmonary arterial hypertension in a primate model of HIV infection. AIDS Res. Hum. Retroviruses,  2019, 35(1), 63-74.
 [http://dx.doi.org/10.1089/aid.2018.0132] [PMID: 30229666]

[56]
Kataoka, H.T.; Hosen, N.; Sonobe, T.; Arita, Y.; Yasui, T.; Masaki, T.; Minami, M.; Inagaki, T.; Miyagawa, S.; Sawa, Y.; Murakami, M.; Kumanogoh, A.; Takihara, Y.K.; Okumura, M.; Kishimoto, T.; Komuro, I.; Shirai, M.; Sakata, Y.; Nakaoka, Y. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc. Natl. Acad. Sci.,  2015, 112(20), E2677-E2686.
 [http://dx.doi.org/10.1073/pnas.1424774112] [PMID: 25941359]

[57]
Le Hiress, M.; Tu, L.; Ricard, N.; Phan, C.; Thuillet, R.; Fadel, E.; Dorfmüller, P.; Montani, D.; de Man, F.; Humbert, M.; Huertas, A.; Guignabert, C. Proinflammatory signature of the dysfunctional endothelium in pulmonary hypertension. Role of the macrophage migration inhibitory factor/CD74 complex. Am. J. Respir. Crit. Care Med.,  2015, 192(8), 983-997.
 [http://dx.doi.org/10.1164/rccm.201402-0322OC] [PMID: 26203495]

[58]
West, J.D.; Chen, X.; Ping, L.; Gladson, S.; Hamid, R.; Lloyd, J.E.; Talati, M. Adverse effects of BMPR2 suppression in macrophages in animal models of pulmonary hypertension. Pulm. Circ.,  2019, 10(1), 2045894019856483.
 [PMID: 31124398]

[59]
Hoffmann, J.; Yin, J.; Kukucka, M.; Yin, N.; Saarikko, I.; Sterner-Kock, A.; Fujii, H.; Leong-Poi, H.; Kuppe, H.; Schermuly, R.T.; Kuebler, W.M. Mast cells promote lung vascular remodelling in pulmonary hypertension. Eur. Respir. J.,  2011, 37(6), 1400-1410.
 [http://dx.doi.org/10.1183/09031936.00043310] [PMID: 21148228]

[60]
Hautefort, A.; Girerd, B.; Montani, D.; Kaminsky, C.S.; Price, L.; Lambrecht, B.N.; Humbert, M.; Perros, F. T-helper 17 cell polarization in pulmonary arterial hypertension. Chest,  2015, 147(6), 1610-1620.
 [http://dx.doi.org/10.1378/chest.14-1678] [PMID: 25429518]

[61]
Mirsaeidi, M.; Mortaz, E.; Omar, H.R.; Camporesi, E.M.; Sweiss, N. Association of neutrophil to lymphocyte ratio and pulmonary hypertension in sarcoidosis patients. Tanaffos,  2016, 15(1), 44-47.
 [PMID: 27403178]

[62]
Aldabbous, L.; Salam, A.V.; McKinnon, T.; Duluc, L.; Zaba, P.J.; Southwood, M.; Ainscough, A.J.; Hadinnapola, C.; Wilkins, M.R.; Toshner, M.; Stothard, W.B. Neutrophil extracellular traps promote angiogenesis. Arterioscler. Thromb. Vasc. Biol.,  2016, 36(10), 2078-2087.
 [http://dx.doi.org/10.1161/ATVBAHA.116.307634] [PMID: 27470511]

[63]
Lee, J.G.; Kay, E.P. Common and distinct pathways for cellular activities in FGF-2 signaling induced by IL-1beta in corneal endothelial cells. Invest. Ophthalmol. Vis. Sci.,  2009, 50(5), 2067-2076.
 [http://dx.doi.org/10.1167/iovs.08-3135] [PMID: 19136710]

[64]
Itoh, A.; Nishihira, J.; Makita, H.; Miyamoto, K.; Yamaguchi, E.; Nishimura, M. Effects of IL-1β, TNF-α, and macrophage migration inhibitory factor on prostacyclin synthesis in rat pulmonary artery smooth muscle cells. Respirology,  2003, 8(4), 467-472.
 [http://dx.doi.org/10.1046/j.1440-1843.2003.00491.x] [PMID: 14629650]

[65]
Courboulin, A.; Tremblay, V.L.; Barrier, M.; Meloche, J.; Jacob, M.H.; Chapolard, M.; Bisserier, M.; Paulin, R.; Lambert, C.; Provencher, S.; Bonnet, S. Krüppel-like Factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension. Respir. Res.,  2011, 12(1), 128.
 [http://dx.doi.org/10.1186/1465-9921-12-128] [PMID: 21951574]

[66]
Savale, L.; Tu, L.; Rideau, D.; Izziki, M.; Maitre, B.; Adnot, S.; Eddahibi, S. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir. Res.,  2009, 10(1), 6.
 [http://dx.doi.org/10.1186/1465-9921-10-6] [PMID: 19173740]

[67]
Steiner, M.K.; Syrkina, O.L.; Kolliputi, N. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res,  2009, 104(2), 236-244.

[68]
Prins, K.W.; Archer, S.L.; Pritzker, M.; Rose, L.; Weir, E.K.; Sharma, A.; Thenappan, T. Interleukin-6 is independently associated with right ventricular function in pulmonary arterial hypertension. J. Heart Lung Transplant.,  2018, 37(3), 376-384.
 [http://dx.doi.org/10.1016/j.healun.2017.08.011] [PMID: 28893516]

[69]
Hagen, M.; Fagan, K.; Steudel, W.; Carr, M.; Lane, K.; Rodman, D.M.; West, J. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2007, 292(6), L1473-L1479.
 [http://dx.doi.org/10.1152/ajplung.00197.2006] [PMID: 17322283]

[70]
Vengethasamy, L.; Hautefort, A.; Tielemans, B.; Belge, C.; Perros, F.; Verleden, S.; Fadel, E.; Van Raemdonck, D.; Delcroix, M.; Quarck, R. BMPRII influences the response of pulmonary microvascular endothelial cells to inflammatory mediators. Pflugers Arch.,  2016, 468(11-12), 1969-1983.
 [http://dx.doi.org/10.1007/s00424-016-1899-1] [PMID: 27816994]

[71]
Golembeski, S.M.; West, J.; Tada, Y.; Fagan, K.A. Interleukin-6 causes mild pulmonary hypertension and augments hypoxia-induced pulmonary hypertension in mice. Chest,  2005, 128(S6), 572S-573S.
 [http://dx.doi.org/10.1378/chest.128.6_suppl.572S-a] [PMID: 16373831]

[72]
Price, L.C.; Caramori, G.; Perros, F.; Meng, C.; Gambaryan, N.; Dorfmuller, P.; Montani, D.; Casolari, P.; Zhu, J.; Dimopoulos, K.; Shao, D.; Girerd, B.; Mumby, S.; Proudfoot, A.; Griffiths, M.; Papi, A.; Humbert, M.; Adcock, I.M.; Wort, S.J. Nuclear factor κ-B is activated in the pulmonary vessels of patients with end-stage idiopathic pulmonary arterial hypertension. PLoS One,  2013, 8(10), e75415.
 [http://dx.doi.org/10.1371/journal.pone.0075415] [PMID: 24124488]

[73]
Raychaudhuri, B.; Dweik, R.; Connors, M.J.; Buhrow, L.; Malur, A.; Drazba, J.; Arroliga, A.C.; Erzurum, S.C.; Kavuru, M.S.; Thomassen, M.J. Nitric oxide blocks nuclear factor-kappaB activation in alveolar macrophages. Am. J. Respir. Cell Mol. Biol.,  1999, 21(3), 311-316.
 [http://dx.doi.org/10.1165/ajrcmb.21.3.3611] [PMID: 10460748]

[74]
Olivetta, E.; Percario, Z.; Fiorucci, G.; Mattia, G.; Schiavoni, I.; Dennis, C.; Jäger, J.; Harris, M.; Romeo, G.; Affabris, E.; Federico, M. HIV-1 Nef induces the release of inflammatory factors from human monocyte/macrophages: Involvement of Nef endocytotic signals and NF-kappa B activation. J. Immunol.,  2003, 170(4), 1716-1727.
 [http://dx.doi.org/10.4049/jimmunol.170.4.1716] [PMID: 12574335]

[75]
Ross, D.J.; Strieter, R.M.; Fishbein, M.C.; Ardehali, A.; Belperio, J.A. Type I immune response cytokine–chemokine cascade is associated with pulmonary arterial hypertension. J. Heart Lung Transplant.,  2012, 31(8), 865-873.
 [http://dx.doi.org/10.1016/j.healun.2012.04.008] [PMID: 22658713]

[76]
Balabanian, K.; Foussat, A.; Dorfmüller, P.; Durand-Gasselin, I.; Capel, F.; Bouchet-Delbos, L.; Portier, A.; Marfaing-Koka, A.; Krzysiek, R.; Rimaniol, A.C.; Simonneau, G.; Emilie, D.; Humbert, M. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2002, 165(10), 1419-1425.
 [http://dx.doi.org/10.1164/rccm.2106007] [PMID: 12016106]

[77]
Dorfmüller, P.; Zarka, V.; Gasselin, D.I.; Monti, G.; Balabanian, K.; Garcia, G.; Capron, F.; Coulomb-Lherminé, A.; Marfaing-Koka, A.; Simonneau, G.; Emilie, D.; Humbert, M. Chemokine RANTES in severe pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2002, 165(4), 534-539.
 [http://dx.doi.org/10.1164/ajrccm.165.4.2012112] [PMID: 11850348]

[78]
Perros, F.; Dorfmüller, P.; Souza, R.; Gasselin, D.I.; Godot, V.; Capel, F.; Adnot, S.; Eddahibi, S.; Mazmanian, M.; Fadel, E.; Hervé, P.; Simonneau, G.; Emilie, D.; Humbert, M. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur. Respir. J.,  2007, 29(5), 937-943.
 [http://dx.doi.org/10.1183/09031936.00104706] [PMID: 17182651]

[79]
Larsen, K.O.; Yndestad, A.; Sjaastad, I.; Løberg, E.M.; Goverud, I.L.; Halvorsen, B.; Jia, J.; Andreassen, A.K.; Husberg, C.; Jonasson, S.; Lipp, M.; Christensen, G.; Aukrust, P.; Skjønsberg, O.H. Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2011, 301(1), L50-L59.
 [http://dx.doi.org/10.1152/ajplung.00048.2010] [PMID: 21498626]

[80]
Amsellem, V.; Lipskaia, L.; Abid, S.; Poupel, L.; Houssaini, A.; Quarck, R.; Marcos, E.; Mouraret, N.; Parpaleix, A.; Bobe, R.; Bobo, G.G.; Saker, M.; Randé, D.J.L.; Gladwin, M.T.; Norris, K.A.; Delcroix, M.; Combadière, C.; Adnot, S. CCR5 as a treatment target in pulmonary arterial hypertension. Circulation,  2014, 130(11), 880-891.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.114.010757] [PMID: 24993099]

[81]
Tian, W.; Jiang, X.; Tamosiuniene, R.; Sung, Y.K.; Qian, J.; Dhillon, G.; Gera, L.; Farkas, L.; Rabinovitch, M.; Zamanian, R.T.; Inayathullah, M.; Fridlib, M.; Rajadas, J.; Golden, P.M.; Voelkel, N.F.; Nicolls, M.R. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci. Transl. Med.,  2013, 5(200), 200ra117.
 [http://dx.doi.org/10.1126/scitranslmed.3006674] [PMID: 23986401]

[82]
Angelini, D.J.; Su, Q.; Kegan, Y.K.; Fan, C.; Skinner, J.T.; Champion, H.C.; Crow, M.T.; Johns, R.A. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) induces the vascular and hemodynamic changes of pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2009, 296(4), L582-L593.
 [http://dx.doi.org/10.1152/ajplung.90526.2008] [PMID: 19136574]

[83]
Goldenberg, N.M.; Hu, Y.; Hu, X.; Volchuk, A.; Zhao, Y.D.; Kucherenko, M.M.; Knosalla, C.; de Perrot, M.; Tracey, K.J.; Al-Abed, Y.; Steinberg, B.E.; Kuebler, W.M. Therapeutic targeting of high-mobility group Box-1 in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2019, 199(12), 1566-1569.
 [http://dx.doi.org/10.1164/rccm.201808-1597LE] [PMID: 30939030]

[84]
Huertas, A.; Tu, L.; Gambaryan, N.; Girerd, B.; Perros, F.; Montani, D.; Fabre, D.; Fadel, E.; Eddahibi, S.; Kaminsky, C.S.; Guignabert, C.; Humbert, M. Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur. Respir. J.,  2012, 40(4), 895-904.
 [http://dx.doi.org/10.1183/09031936.00159911] [PMID: 22362850]

[85]
Huertas, A.; Tu, L.; Humbert, M.; Guignabert, C. Chronic inflammation within the vascular wall in pulmonary arterial hypertension: more than a spectator. Cardiovasc. Res.,  2020, 116(5), 885-893.
 [http://dx.doi.org/10.1093/cvr/cvz308] [PMID: 31813986]

[86]
Arends, S.J.; Damoiseaux, J.G.M.C.; Duijvestijn, A.M.; Palmans, D.L.; Vroomen, M.; Boomars, K.A.; Rocca, B.L.H.P.; Reutelingsperger, C.P.M.; Tervaert, C.J.W.; van Paassen, P. Immunoglobulin G anti-endothelial cell antibodies: Inducers of endothelial cell apoptosis in pulmonary arterial hypertension? Clin. Exp. Immunol.,  2013, 174(3), 433-440.
 [http://dx.doi.org/10.1111/cei.12166] [PMID: 23815467]

[87]
Bordron, A.; Dueymes, M.; Levy, Y.; Jamin, C.; Leroy, J.P.; Piette, J.C.; Shoenfeld, Y.; Youinou, P.Y. The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis. J. Clin. Invest.,  1998, 101(10), 2029-2035.
 [http://dx.doi.org/10.1172/JCI2261] [PMID: 9593758]

[88]
Carvalho, D.; Savage, C.O.; Black, C.M.; Pearson, J.D. IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J. Clin. Invest.,  1996, 97(1), 111-119.
 [http://dx.doi.org/10.1172/JCI118377] [PMID: 8550821]

[89]
Dib, H.; Tamby, M.C.; Bussone, G.; Regent, A.; Berezné, A.; Lafine, C.; Broussard, C.; Simonneau, G.; Guillevin, L.; Witko-Sarsat, V.; Humbert, M.; Mouthon, L. Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur. Respir. J.,  2012, 39(6), 1405-1414.
 [http://dx.doi.org/10.1183/09031936.00181410] [PMID: 22005913]

[90]
Shu, T.; Xing, Y.; Wang, J. Autoimmunity in pulmonary arterial hypertension: Evidence for local immunoglobulin production. Front. Cardiovasc. Med.,  2021, 8, 680109.
 [http://dx.doi.org/10.3389/fcvm.2021.680109] [PMID: 34621794]

[91]
Tamby, M.C.; Chanseaud, Y.; Humbert, M.; Fermanian, J.; Guilpain, P.; de-la-Lefebvre, G.P.P.; Brunet, S.; Servettaz, A.; Weill, B.; Simonneau, G.; Guillevin, L.; Boissier, M.C.; Mouthon, L. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax,  2005, 60(9), 765-772.
 [http://dx.doi.org/10.1136/thx.2004.029082] [PMID: 16135682]

[92]
Tamby, M.C.; Humbert, M.; Guilpain, P.; Servettaz, A.; Dupin, N.; Christner, J.J.; Simonneau, G.; Fermanian, J.; Weill, B.; Guillevin, L.; Mouthon, L. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur. Respir. J.,  2006, 28(4), 799-807.
 [http://dx.doi.org/10.1183/09031936.06.00152705] [PMID: 16774952]

[93]
Perros, F.; Dorfmüller, P.; Montani, D.; Hammad, H.; Waelput, W.; Girerd, B.; Raymond, N.; Mercier, O.; Mussot, S.; Cohen-Kaminsky, S.; Humbert, M.; Lambrecht, B.N. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2012, 185(3), 311-321.
 [http://dx.doi.org/10.1164/rccm.201105-0927OC] [PMID: 22108206]

[94]
Le Pavec, J.; Humbert, M.; Mouthon, L.; Hassoun, P.M. Systemic sclerosis-associated pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2010, 181(12), 1285-1293.
 [http://dx.doi.org/10.1164/rccm.200909-1331PP] [PMID: 20194816]

[95]
Liu, X.D.; Guo, S.Y.; Yang, L.L.; Zhang, X.L.; Fu, W.Y.; Wang, X.F. Anti-endothelial cell antibodies in connective tissue diseases associated with pulmonary arterial hypertension. J. Thorac. Dis.,  2014, 6(5), 497-502.
 [PMID: 24822109]

[96]
Mathai, S.C.; Hassoun, P.M. Pulmonary arterial hypertension in connective tissue diseases. Heart Fail. Clin.,  2012, 8(3), 413-425.
 [http://dx.doi.org/10.1016/j.hfc.2012.04.001] [PMID: 22748903]

[97]
Muñoz, L.E.; Janko, C.; Schulze, C.; Schorn, C.; Sarter, K.; Schett, G.; Herrmann, M. Autoimmunity and chronic inflammation — Two clearance-related steps in the etiopathogenesis of SLE. Autoimmun. Rev.,  2010, 10(1), 38-42.
 [http://dx.doi.org/10.1016/j.autrev.2010.08.015] [PMID: 20817127]

[98]
Rother, N.; van der Vlag, J. Disturbed T cell signaling and altered Th17 and regulatory T cell subsets in the pathogenesis of systemic lupus erythematosus. Front. Immunol.,  2015, 6, 610.
 [http://dx.doi.org/10.3389/fimmu.2015.00610] [PMID: 26648939]

[99]
Terrier, B.; Tamby, M.C.; Camoin, L.; Guilpain, P.; Broussard, C.; Bussone, G.; Yaïci, A.; Hotellier, F.; Simonneau, G.; Guillevin, L.; Humbert, M.; Mouthon, L. Identification of target antigens of antifibroblast antibodies in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2008, 177(10), 1128-1134.
 [http://dx.doi.org/10.1164/rccm.200707-1015OC] [PMID: 18276943]

[100]
Zamanian, R.T.; Badesch, D.; Chung, L.; Domsic, R.T.; Medsger, T.; Pinckney, A.; Keyes-Elstein, L.; D’Aveta, C.; Spychala, M.; White, R.J.; Hassoun, P.M.; Torres, F.; Sweatt, A.J.; Molitor, J.A.; Khanna, D.; Maecker, H.; Welch, B.; Goldmuntz, E.; Nicolls, M.R. Safety and efficacy of b-cell depletion with rituximab for the treatment of systemic sclerosis–associated pulmonary arterial hypertension: A multicenter, double-blind, randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med.,  2021, 204(2), 209-221.
 [http://dx.doi.org/10.1164/rccm.202009-3481OC] [PMID: 33651671]

[101]
Jones, R.J.; De Bie, E.M.D.D.; Groves, E.; Zalewska, K.I.; Swietlik, E.M.; Treacy, C.M.; Martin, J.M.; Polwarth, G.; Li, W.; Guo, J.; Baxendale, H.E.; Coleman, S.; Savinykh, N.; Coghlan, J.G.; Corris, P.A.; Howard, L.S.; Johnson, M.K.; Church, C.; Kiely, D.G.; Lawrie, A.; Lordan, J.L.; Ross, M.R.V.; Zaba, P.J.; Wilkins, M.R.; Wort, S.J.; Fiorillo, E.; Orrù, V.; Cucca, F.; Rhodes, C.J.; Gräf, S.; Morrell, N.W.; McKinney, E.F.; Wallace, C.; Toshner, M.; Bleda, M.; Hadinnapola, C.; Haimel, M.; Auckland, K.; Tilly, T.; Martin, J.M.; Yates, K.; Treacy, C.M.; Day, M.; Greenhalgh, A.; Shipley, D.; Irvine, V.; Kennedy, F.; Moledina, S.; MacDonald, L.; Tamvaki, E.; Barnes, A.; Cookson, V.; Chentouf, L.; Ali, S.; Othman, S.; Ranganathan, L.; Simon, J.; Gibbs, R.; Gummadi, M.; DaCosta, R.; Pinguel, J.; Dormand, N.; Parker, A.; Stokes, D.; Ghedia, D.; Tan, Y.; Ngcozana, T.; Wanjiku, I.; Polwarth, G.; Cannon, J.; Sheares, K.K.; Taboda, D.; Ross, M.R.V.; Suntharalingam, J.; Grover, M.; Kirby, A.; Trembath, R. Autoimmunity is a significant feature of idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2022, 206(1), 81-93.
 [http://dx.doi.org/10.1164/rccm.202108-1919OC] [PMID: 35316153]

[102]
Andruska, A.; Spiekerkoetter, E. Consequences of BMPR2 deficiency in the pulmonary vasculature and beyond: Contributions to pulmonary arterial hypertension. Int. J. Mol. Sci.,  2018, 19(9), 2499.
 [http://dx.doi.org/10.3390/ijms19092499] [PMID: 30149506]

[103]
de Caestecker, M. The transforming growth factor-β superfamily of receptors. Cytokine Growth Factor Rev.,  2004, 15(1), 1-11.
 [http://dx.doi.org/10.1016/j.cytogfr.2003.10.004] [PMID: 14746809]

[104]
Tielemans, B.; Delcroix, M.; Belge, C.; Quarck, R. TGFβ and BMPRII signalling pathways in the pathogenesis of pulmonary arterial hypertension. Drug Discov. Today,  2019, 24(3), 703-716.
 [http://dx.doi.org/10.1016/j.drudis.2018.12.001] [PMID: 30529762]

[105]
Fan, Y.; Gu, X.; Zhang, J.; Sinn, K.; Klepetko, W.; Wu, N.; Foris, V.; Solymosi, P.; Kwapiszewska, G.; Kuebler, W.M. TWIST1 drives smooth muscle cell proliferation in pulmonary hypertension via loss of GATA-6 and BMPR2. Am. J. Respir. Crit. Care Med.,  2020, 202(9), 1283-1296.
 [http://dx.doi.org/10.1164/rccm.201909-1884OC] [PMID: 32692930]

[106]
Upton, P.D.; Morrell, N.W. The transforming growth factor-β–bone morphogenetic protein type signalling pathway in pulmonary vascular homeostasis and disease. Exp. Physiol.,  2013, 98(8), 1262-1266.
 [http://dx.doi.org/10.1113/expphysiol.2012.069104] [PMID: 23645549]

[107]
Burton, V.J.; Ciuclan, L.I.; Holmes, A.M.; Rodman, D.M.; Walker, C.; Budd, D.C. Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function. Blood,  2011, 117(1), 333-341.
 [http://dx.doi.org/10.1182/blood-2010-05-285973] [PMID: 20724539]

[108]
Johnson, J.A.; Hemnes, A.R.; Perrien, D.S.; Schuster, M.; Robinson, L.J.; Gladson, S.; Loibner, H.; Bai, S.; Blackwell, T.R.; Tada, Y.; Harral, J.W.; Talati, M.; Lane, K.B.; Fagan, K.A.; West, J. Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2012, 302(5), L474-L484.
 [http://dx.doi.org/10.1152/ajplung.00202.2011] [PMID: 22180660]

[109]
Davies, R.J.; Holmes, A.M.; Deighton, J.; Long, L.; Yang, X.; Barker, L.; Walker, C.; Budd, D.C.; Upton, P.D.; Morrell, N.W. BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2012, 302(6), L604-L615.
 [http://dx.doi.org/10.1152/ajplung.00309.2011] [PMID: 22227206]

[110]
Zhang, S.; Fantozzi, I.; Tigno, D.D.; Yi, E.S.; Platoshyn, O.; Thistlethwaite, P.A.; Kriett, J.M.; Yung, G.; Rubin, L.J.; Yuan, J.X.J. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2003, 285(3), L740-L754.
 [http://dx.doi.org/10.1152/ajplung.00284.2002] [PMID: 12740218]

[111]
Din, S.; Sarathchandra, P.; Yacoub, M.H.; Chester, A.H. Interaction between bone morphogenetic proteins and endothelin-1 in human pulmonary artery smooth muscle. Vascul. Pharmacol.,  2009, 51(5-6), 344-349.
 [http://dx.doi.org/10.1016/j.vph.2009.09.001] [PMID: 19786120]

[112]
Machado, R.D.; Pauciulo, M.W.; Fretwell, N.; Veal, C.; Thomson, J.R.; Güell, V.C.; Aldred, M.; Brannon, C.A.; Trembath, R.C.; Nichols, W.C. A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. Genomics,  2000, 68(2), 220-228.
 [http://dx.doi.org/10.1006/geno.2000.6291] [PMID: 10964520]

[113]
Deng, Z.; Morse, J.H.; Slager, S.L.; Cuervo, N.; Moore, K.J.; Venetos, G.; Kalachikov, S.; Cayanis, E.; Fischer, S.G.; Barst, R.J.; Hodge, S.E.; Knowles, J.A. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am. J. Hum. Genet.,  2000, 67(3), 737-744.
 [http://dx.doi.org/10.1086/303059] [PMID: 10903931]

[114]
Lane, K.B.; Machado, R.D.; Pauciulo, M.W.; Thomson, J.R.; Phillips, J.A., III; Loyd, J.E.; Nichols, W.C.; Trembath, R.C.; Trembath, R.C. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nat. Genet.,  2000, 26(1), 81-84.
 [http://dx.doi.org/10.1038/79226] [PMID: 10973254]

[115]
Chalmers, S.J.; Murphy, S.J.; Thompson, L.L.; Hoppman, N.L.; Smadbeck, J.B.; Balcom, J.R.; Harris, F.R.; Frantz, R.P.; Vasmatzis, G.; E Wylam, M. Mate-pair sequencing identifies a cryptic BMPR2 mutation in hereditary pulmonary arterial hypertension. Pulm. Circ.,  2021, 10(3), 2045894020933081.
 [PMID: 34290857]

[116]
Machado, R.D.; Southgate, L.; Eichstaedt, C.A.; Aldred, M.A.; Austin, E.D.; Best, D.H.; Chung, W.K.; Benjamin, N.; Elliott, C.G.; Eyries, M.; Fischer, C.; Gräf, S.; Hinderhofer, K.; Humbert, M.; Keiles, S.B.; Loyd, J.E.; Morrell, N.W.; Newman, J.H.; Soubrier, F.; Trembath, R.C.; Viales, R.R.; Grünig, E. Pulmonary arterial hypertension: A current perspective on established and emerging molecular genetic defects. Hum. Mutat.,  2015, 36(12), 1113-1127.
 [http://dx.doi.org/10.1002/humu.22904] [PMID: 26387786]

[117]
Southgate, L.; Machado, R.D.; Gräf, S.; Morrell, N.W. Molecular genetic framework underlying pulmonary arterial hypertension. Nat. Rev. Cardiol.,  2020, 17(2), 85-95.
 [http://dx.doi.org/10.1038/s41569-019-0242-x] [PMID: 31406341]

[118]
Larkin, E.K.; Newman, J.H.; Austin, E.D.; Hemnes, A.R.; Wheeler, L.; Robbins, I.M.; West, J.D.; Phillips, J.A., III; Hamid, R.; Loyd, J.E. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2012, 186(9), 892-896.
 [http://dx.doi.org/10.1164/rccm.201205-0886OC] [PMID: 22923661]

[119]
Morrell, N.W.; Aldred, M.A.; Chung, W.K.; Elliott, C.G.; Nichols, W.C.; Soubrier, F.; Trembath, R.C.; Loyd, J.E. Genetics and genomics of pulmonary arterial hypertension. Eur. Respir. J.,  2019, 53(1), 1801899.
 [http://dx.doi.org/10.1183/13993003.01899-2018] [PMID: 30545973]

[120]
Evans, J.D.W.; Girerd, B.; Montani, D.; Wang, X.J.; Galiè, N.; Austin, E.D.; Elliott, G.; Asano, K.; Grünig, E.; Yan, Y.; Jing, Z.C.; Manes, A.; Palazzini, M.; Wheeler, L.A.; Nakayama, I.; Satoh, T.; Eichstaedt, C.; Hinderhofer, K.; Wolf, M.; Rosenzweig, E.B.; Chung, W.K.; Soubrier, F.; Simonneau, G.; Sitbon, O.; Gräf, S.; Kaptoge, S.; Di Angelantonio, E.; Humbert, M.; Morrell, N.W. BMPR2 mutations and survival in pulmonary arterial hypertension: An individual participant data meta-analysis. Lancet Respir. Med.,  2016, 4(2), 129-137.
 [http://dx.doi.org/10.1016/S2213-2600(15)00544-5] [PMID: 26795434]

[121]
Chaouat, A.; Coulet, F.; Favre, C.; Simonneau, G.; Weitzenblum, E.; Soubrier, F.; Humbert, M. Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax,  2004, 59(5), 446-448.
 [http://dx.doi.org/10.1136/thx.2003.11890] [PMID: 15115879]

[122]
Trembath, R.C.; Thomson, J.R.; Machado, R.D.; Morgan, N.V.; Atkinson, C.; Winship, I.; Simonneau, G.; Galie, N.; Loyd, J.E.; Humbert, M.; Nichols, W.C.; Berg, J.; Manes, A.; McGaughran, J.; Pauciulo, M.; Wheeler, L.; Morrell, N.W. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N. Engl. J. Med.,  2001, 345(5), 325-334.
 [http://dx.doi.org/10.1056/NEJM200108023450503] [PMID: 11484689]

[123]
Gräf, S.; Haimel, M.; Bleda, M.; Hadinnapola, C.; Southgate, L.; Li, W.; Hodgson, J.; Liu, B.; Salmon, R.M.; Southwood, M.; Machado, R.D.; Martin, J.M.; Treacy, C.M.; Yates, K.; Daugherty, L.C.; Shamardina, O.; Whitehorn, D.; Holden, S.; Aldred, M.; Bogaard, H.J.; Church, C.; Coghlan, G.; Condliffe, R.; Corris, P.A.; Danesino, C.; Eyries, M.; Gall, H.; Ghio, S.; Ghofrani, H.A.; Gibbs, J.S.R.; Girerd, B.; Houweling, A.C.; Howard, L.; Humbert, M.; Kiely, D.G.; Kovacs, G.; Ross, M.R.V.; Moledina, S.; Montani, D.; Newnham, M.; Olschewski, A.; Olschewski, H.; Peacock, A.J.; Pepke-Zaba, J.; Prokopenko, I.; Rhodes, C.J.; Scelsi, L.; Seeger, W.; Soubrier, F.; Stein, D.F.; Suntharalingam, J.; Swietlik, E.M.; Toshner, M.R.; van Heel, D.A.; Noordegraaf, V.A.; Waisfisz, Q.; Wharton, J.; Wort, S.J.; Ouwehand, W.H.; Soranzo, N.; Lawrie, A.; Upton, P.D.; Wilkins, M.R.; Trembath, R.C.; Morrell, N.W. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nat. Commun.,  2018, 9(1), 1416.
 [http://dx.doi.org/10.1038/s41467-018-03672-4] [PMID: 29650961]

[124]
Nasim, M.T.; Ogo, T.; Ahmed, M.; Randall, R.; Chowdhury, H.M.; Snape, K.M.; Bradshaw, T.Y.; Southgate, L.; Lee, G.J.; Jackson, I.; Lord, G.M.; Gibbs, J.S.R.; Wilkins, M.R.; Ogo, O.K.; Nakamura, K.; Girerd, B.; Coulet, F.; Soubrier, F.; Humbert, M.; Morrell, N.W.; Trembath, R.C.; Machado, R.D. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum. Mutat.,  2011, 32(12), 1385-1389.
 [http://dx.doi.org/10.1002/humu.21605] [PMID: 21898662]

[125]
Austin, E.D.; Ma, L.; LeDuc, C.; Rosenzweig, B.E.; Borczuk, A.; Phillips, J.A., III; Palomero, T.; Sumazin, P.; Kim, H.R.; Talati, M.H.; West, J.; Loyd, J.E.; Chung, W.K. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ. Cardiovasc. Genet.,  2012, 5(3), 336-343.
 [http://dx.doi.org/10.1161/CIRCGENETICS.111.961888] [PMID: 22474227]

[126]
Ma, L.; Roman-Campos, D.; Austin, E.D.; Eyries, M.; Sampson, K.S.; Soubrier, F.; Germain, M.; Trégouët, D.A.; Borczuk, A.; Rosenzweig, E.B.; Girerd, B.; Montani, D.; Humbert, M.; Loyd, J.E.; Kass, R.S.; Chung, W.K. A novel channelopathy in pulmonary arterial hypertension. N. Engl. J. Med.,  2013, 369(4), 351-361.
 [http://dx.doi.org/10.1056/NEJMoa1211097] [PMID: 23883380]

[127]
Zhu, N.; Jauregui, G.C.; Welch, C.L.; Ma, L.; Qi, H.; King, A.K.; Krishnan, U.; Rosenzweig, E.B.; Ivy, D.D.; Austin, E.D.; Hamid, R.; Nichols, W.C.; Pauciulo, M.W.; Lutz, K.A.; Sawle, A.; Reid, J.G.; Overton, J.D.; Baras, A.; Dewey, F.; Shen, Y.; Chung, W.K. Exome sequencing in children with pulmonary arterial hypertension demonstrates differences compared with adults. Circ. Genom. Precis. Med.,  2018, 11(4), e001887.
 [http://dx.doi.org/10.1161/CIRCGEN.117.001887] [PMID: 29631995]

[128]
Best, D.H.; Sumner, K.L.; Austin, E.D.; Chung, W.K.; Brown, L.M.; Borczuk, A.C.; Rosenzweig, E.B.; Toydemir, B.P.; Mao, R.; Cahill, B.C.; Tazelaar, H.D.; Leslie, K.O.; Hemnes, A.R.; Robbins, I.M.; Elliott, C.G. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest,  2014, 145(2), 231-236.
 [http://dx.doi.org/10.1378/chest.13-2366] [PMID: 24135949]

[129]
Eyries, M.; Montani, D.; Girerd, B.; Perret, C.; Leroy, A.; Lonjou, C.; Chelghoum, N.; Coulet, F.; Bonnet, D.; Dorfmüller, P.; Fadel, E.; Sitbon, O.; Simonneau, G.; Tregouët, D.A.; Humbert, M.; Soubrier, F. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat. Genet.,  2014, 46(1), 65-69.
 [http://dx.doi.org/10.1038/ng.2844] [PMID: 24292273]

[130]
Spiekerkoetter, E.; Sung, Y.K.; Sudheendra, D.; Scott, V.; Del Rosario, P.; Bill, M.; Haddad, F.; Long-Boyle, J.; Hedlin, H.; Zamanian, R.T. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur. Respir. J.,  2017, 50(3), 1602449.
 [http://dx.doi.org/10.1183/13993003.02449-2016] [PMID: 28893866]

[131]
Long, L.; Yang, X.; Southwood, M.; Lu, J.; Marciniak, S.J.; Dunmore, B.J.; Morrell, N.W. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circ. Res.,  2013, 112(8), 1159-1170.
 [http://dx.doi.org/10.1161/CIRCRESAHA.111.300483] [PMID: 23446737]

[132]
Long, L.; Ormiston, M.L.; Yang, X.; Southwood, M.; Gräf, S.; Machado, R.D.; Mueller, M.; Kinzel, B.; Yung, L.M.; Wilkinson, J.M.; Moore, S.D.; Drake, K.M.; Aldred, M.A.; Yu, P.B.; Upton, P.D.; Morrell, N.W. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat. Med.,  2015, 21(7), 777-785.
 [http://dx.doi.org/10.1038/nm.3877] [PMID: 26076038]

[133]
Owen, N.E.; Alexander, G.J.; Sen, S.; Bunclark, K.; Polwarth, G.; Pepke-Zaba, J.; Davenport, A.P.; Morrell, N.W.; Upton, P.D. Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis. EBioMedicine,  2020, 56, 102794.
 [http://dx.doi.org/10.1016/j.ebiom.2020.102794] [PMID: 32454407]

[134]
Humbert, M.; McLaughlin, V.; Gibbs, J.S.R.; Gomberg-Maitland, M.; Hoeper, M.M.; Preston, I.R.; Souza, R.; Waxman, A.; Escribano Subias, P.; Feldman, J.; Meyer, G.; Montani, D.; Olsson, K.M.; Manimaran, S.; Barnes, J.; Linde, P.G.; de Pena, O.J.; Badesch, D.B.; Investigators, P.T. Sotatercept for the treatment of pulmonary arterial hypertension. N. Engl. J. Med.,  2021, 384(13), 1204-1215.
 [http://dx.doi.org/10.1056/NEJMoa2024277] [PMID: 33789009]

[135]
Hoeper, M.M.; Badesch, D.B.; Ghofrani, H.A.; Gibbs, J.S.R.; Gomberg-Maitland, M.; McLaughlin, V.V.; Preston, I.R.; Souza, R.; Waxman, A.B.; Grünig, E.; Kopeć, G.; Meyer, G.; Olsson, K.M.; Rosenkranz, S.; Xu, Y.; Miller, B.; Fowler, M.; Butler, J.; Koglin, J.; de Pena, O.J.; Humbert, M.; Investigators, S.T. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N. Engl. J. Med.,  2023, 388(16), 1478-1490.
 [http://dx.doi.org/10.1056/NEJMoa2213558] [PMID: 36877098]

[136]
Schermuly, R.T.; Dony, E.; Ghofrani, H.A.; Pullamsetti, S.; Savai, R.; Roth, M.; Sydykov, A.; Lai, Y.J.; Weissmann, N.; Seeger, W.; Grimminger, F. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest.,  2005, 115(10), 2811-2821.
 [http://dx.doi.org/10.1172/JCI24838] [PMID: 16200212]

[137]
Perros, F.; Montani, D.; Dorfmüller, P.; Gasselin, D.I.; Tcherakian, C.; Le Pavec, J.; Mazmanian, M.; Fadel, E.; Mussot, S.; Mercier, O.; Hervé, P.; Emilie, D.; Eddahibi, S.; Simonneau, G.; Souza, R.; Humbert, M. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2008, 178(1), 81-88.
 [http://dx.doi.org/10.1164/rccm.200707-1037OC] [PMID: 18420966]

[138]
Patterson, K.C.; Weissmann, A.; Ahmadi, T.; Farber, H.W. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann. Intern. Med.,  2006, 145(2), 152-153.
 [http://dx.doi.org/10.7326/0003-4819-145-2-200607180-00020] [PMID: 16847299]

[139]
Souza, R.; Sitbon, O.; Parent, F.; Simonneau, G.; Humbert, M. Long term imatinib treatment in pulmonary arterial hypertension. Thorax,  2006, 61(8), 736.
 [http://dx.doi.org/10.1136/thx.2006.064097] [PMID: 16877696]

[140]
Hoeper, M.M.; Barst, R.J.; Bourge, R.C.; Feldman, J.; Frost, A.E.; Galié, N.; Sánchez, G.M.A.; Grimminger, F.; Grünig, E.; Hassoun, P.M.; Morrell, N.W.; Peacock, A.J.; Satoh, T.; Simonneau, G.; Tapson, V.F.; Torres, F.; Lawrence, D.; Quinn, D.A.; Ghofrani, H.A. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation,  2013, 127(10), 1128-1138.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.112.000765] [PMID: 23403476]

[141]
Izikki, M.; Guignabert, C.; Fadel, E.; Humbert, M.; Tu, L.; Zadigue, P.; Dartevelle, P.; Simonneau, G.; Adnot, S.; Maitre, B.; Raffestin, B.; Eddahibi, S. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J. Clin. Invest.,  2009, 119(3), 512-523.
 [http://dx.doi.org/10.1172/JCI35070] [PMID: 19197140]

[142]
Dahal, B.K.; Cornitescu, T.; Tretyn, A.; Pullamsetti, S.S.; Kosanovic, D.; Dumitrascu, R.; Ghofrani, H.A.; Weissmann, N.; Voswinckel, R.; Banat, G.A.; Seeger, W.; Grimminger, F.; Schermuly, R.T. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am. J. Respir. Crit. Care Med.,  2010, 181(2), 158-167.
 [http://dx.doi.org/10.1164/rccm.200811-1682OC] [PMID: 19850946]

[143]
Klein, M.; Schermuly, R.T.; Ellinghaus, P.; Milting, H.; Riedl, B.; Nikolova, S.; Pullamsetti, S.S.; Weissmann, N.; Dony, E.; Savai, R.; Ghofrani, H.A.; Grimminger, F.; Busch, A.E.; Schäfer, S. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation,  2008, 118(20), 2081-2090.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.108.779751] [PMID: 18955668]

[144]
Swietlik, E.M.; Greene, D.; Zhu, N.; Megy, K.; Cogliano, M.; Rajaram, S.; Pandya, D.; Tilly, T.; Lutz, K.A.; Welch, C.C.L.; Pauciulo, M.W.; Southgate, L.; Martin, J.M.; Treacy, C.M.; Penkett, C.J.; Stephens, J.C.; Bogaard, H.J.; Church, C.; Coghlan, G.; Coleman, A.W.; Condliffe, R.; Eichstaedt, C.A.; Eyries, M.; Gall, H.; Ghio, S.; Girerd, B.; Grünig, E.; Holden, S.; Howard, L.; Humbert, M.; Kiely, D.G.; Kovacs, G.; Lordan, J.; Machado, R.D.; Ross, M.R.V.; McCabe, C.; Moledina, S.; Montani, D.; Olschewski, H.; Pepke-Zaba, J.; Price, L.; Rhodes, C.J.; Seeger, W.; Soubrier, F.; Suntharalingam, J.; Toshner, M.R.; Noordegraaf, V.A.; Wharton, J.; Wild, J.M.; Wort, S.J.; Lawrie, A.; Wilkins, M.R.; Trembath, R.C.; Shen, Y.; Chung, W.K.; Swift, A.J.; Nichols, W.C.; Morrell, N.W.; Gräf, S.; Abbs, S.; Abulhoul, L.; Adlard, J.; Ahmed, M.; Aitman, T.J.; Alachkar, H.; Allsup, D.J.; Ancliff, P.; Antrobus, R.; Armstrong, R.; Arno, G.; Ashford, S.; Astle, W.J.; Attwood, A.; Aurora, P.; Babbs, C.; Bacchelli, C.; Bakchoul, T.; Banka, S.; Bariana, T.; Barwell, J.; Batista, J.; Baxendale, H.E.; Beales, P.L.; Bennett, D.L.; Bierzynska, A.; Biss, T.; Bitner-Glindzicz, M.A.K.; Black, G.C.; Bleda, M.; Blesneac, I.; Bockenhauer, D.; Boyce, S.; Bradley, J.R.; Breen, G.; Brennan, P.; Brewer, C.; Brown, M.; Browning, A.C.; Browning, M.J.; Buchan, R.J.; Buckland, M.S.; Bueser, T.; Diz, C.B.; Burn, J.; Burns, S.O.; Burren, O.S.; Burrows, N.; Campbell, C.; Carr-White, G.; Carss, K.; Casey, R.; Caulfield, M.J.; Chambers, J.; Chambers, J.; Chan, M.M.Y.; Cheng, F.; Chinnery, P.F.; Chitre, M.; Christian, M.T.; Smith, C.J.; Cleary, M.; Brod, N.C.; Colby, E.; Cole, T.R.P.; Collins, J.; Collins, P.W.; Compton, C.J.; Cook, H.T.; Cook, S.; Cooper, N.; Corris, P.A.; Curry, N.S.; Daniels, M.J.; Dattani, M.; Daugherty, L.C.; Davis, J.; De Soyza, A.; Deevi, S.V.V.; Dent, T.; Deshpande, C.; Dewhurst, E.F.; Dixon, P.H.; Douzgou, S.; Downes, K.; Drazyk, A.M.; Drewe, E.; Duarte, D.; Dutt, T.; Edgar, J.D.M.; Edwards, K.; Egner, W.; Ekani, M.N.; Elliott, P.; Erber, W.N.; Erwood, M.; Estiu, M.C.; Evans, D.G.; Evans, G.; Everington, T.; Fassihi, H.; Favier, R.; Fletcher, D.; Flinter, F.A.; Floto, R.A.; Fowler, T.; Fox, J.; Frary, A.J.; French, C.E.; Freson, K.; Frontini, M.; Furnell, A.; Gale, D.P.; Ganesan, V.; Gattens, M.; Ghofrani, H-A.; Gibbs, J.S.R.; Gibson, K.; Gilmour, K.C.; Gleadall, N.S.; Goddard, S.; Gomez, K.; Gordins, P.; Gosal, D.; Graham, J.; Grassi, L.; Greenhalgh, L.; Greinacher, A.; Gresele, P.; Griffiths, P.; Grigoriadou, S.; Grozeva, D.; Gurnell, M.; Hackett, S.; Hadinnapola, C.; Hague, R.; Hague, W.M.; Haimel, M.; Hall, M.; Hanson, H.L.; Haque, E.; Harkness, K.; Harper, A.R.; Harris, C.L.; Hart, D.; Hassan, A.; Hayman, G.; Henderson, A.; Herwadkar, A.; Hoffman, J.; Horvath, R.; Houlden, H.; Houweling, A.C.; Hu, F.; Hudson, G.; Huissoon, A.P.; Hurles, M.; Irving, M.; Izatt, L.; James, R.; Johnson, S.A.; Jolles, S.; Jolley, J.; Josifova, D.; Jurkute, N.; Kasanicki, M.A.; Kazkaz, H.; Kazmi, R.; Kelleher, P.; Kelly, A.M.; Kelsall, W.; Kempster, C.; Kingston, N.; Koelling, N.; Kostadima, M.; Koziell, A.; Kreuzhuber, R.; Kuijpers, T.W.; Kumar, A.; Kumararatne, D.; Kurian, M.A.; Laffan, M.A.; Lalloo, F.; Lambert, M.; Allen, H.L.; Layton, D.M.; Lentaigne, C.; Lester, T.; Levine, A.P.; Linger, R.; Longhurst, H.; Lorenzo, L.E.; Louka, E.; Lyons, P.A.; Madan, B.; Maher, E.R.; Maimaris, J.; Malka, S.; Mangles, S.; Mapeta, R.; Marchbank, K.J.; Marks, S.; Markus, H.S.; Marschall, H-U.; Marshall, A.; Mathias, M.; Matthews, E.; Maxwell, H.; McAlinden, P.; McCarthy, M.I.; McKinney, H.; Meacham, S.; Mead, A.J.; Mehta, S.G.; Michaelides, M.; Millar, C.; Mohammed, S.N.; Moore, A.T.; Mozere, M.; Muir, K.W.; Mumford, A.D.; Nemeth, A.H.; Newman, W.G.; Newnham, M.; Noorani, S.; Nurden, P.; O’Sullivan, J.; Obaji, S.; Odhams, C.; Okoli, S.; Olschewski, A.; Ong, K.R.; Oram, S.H.; Ormondroyd, E.; Ouwehand, W.H.; Palles, C.; Papadia, S.; Park, S-M.; Parry, D.; Patel, S.; Paterson, J.; Peacock, A.; Pearce, S.H.; Peerlinck, K.; Petersen, R.; Pilkington, C.; Poole, K.E.S.; Psaila, B.; Pyle, A.; Quinton, R.; Rahman, S.; Rao, A.; Raymond, F.L.; Rayner-Matthews, P.J.; Rendon, A.; Renton, T.; Rice, A.S.C.; Richter, A.; Robert, L.; Roberts, I.; Rose, S.J.; Ross-Russell, R.; Roughley, C.; Roy, N.B.A.; Ruddy, D.M.; Alavijeh, S.O.; Saleem, M.A.; Samani, N.; Samarghitean, C.; Juan, S.A.; Sargur, R.B.; Sarkany, R.N.; Satchell, S.; Savic, S.; Sayer, G.; Sayer, J.A.; Scelsi, L.; Schaefer, A.M.; Schulman, S.; Scott, R.; Scully, M.; Searle, C.; Sen, A.; Sewell, W.A.C.; Seyres, D.; Shah, N.; Shamardina, O.; Shapiro, S.E.; Shaw, A.C.; Sibson, K.; Side, L.; Simeoni, I.; Simpson, M.A.; Sims, M.C.; Sivapalaratnam, S.; Smedley, D.; Smith, K.R.; Smith, K.G.C.; Snape, K.; Soranzo, N.; Spasic-Boskovic, O.; Staines, S.; Staples, E.; Stark, H.; Stirrups, K.E.; Stuckey, A.; Syrris, P.; Tait, R.C.; Talks, K.; Tan, R.Y.Y.; Taylor, J.C.; Taylor, J.M.; Thaventhiran, J.E.; Themistocleous, A.C.; Thomas, D.; Thomas, E.; Thomas, M.J.; Thomas, P.; Thomson, K.; Thrasher, A.J.; Thys, C.; Tischkowitz, M.; Titterton, C.; Toh, C-H.; Tomlinson, I.P.; Traylor, M.; Treadaway, P.; Tuna, S.; Turro, E.; Twiss, P.; Vale, T.; Van Geet, C.; van Zuydam, N.; Vandersteen, A.M.; Lopez, V.M.; von Ziegenweidt, J.; Wagner, A.; Waisfisz, Q.; Walker, N.; Walker, S.M.; Ware, J.S.; Watkins, H.; Watt, C.; Webster, A.R.; Wedderburn, L.; Wei, W.; Welch, S.B.; Wessels, J.; Westbury, S.K.; Westwood, J-P.; Whitehorn, D.; Whitworth, J.; Wilkie, A.O.M.; Williamson, C.; Wilson, B.T.; Wong, E.K.S.; Wood, N.; Wood, Y.; Woods, C.G.; Woodward, E.R.; Worth, A.; Wright, M.; Yates, K.; Yong, P.F.K.; Young, T.; Yu, P.; Yu-Wai-Man, P.; Zlamalova, E.; Hirsch, R.; White, R.J.; Simon, M.; Badesch, D.; Rosenzweig, E.; Burger, C.; Chakinala, M.; Thenappan, T.; Elliott, G.; Simms, R.; Farber, H.; Frantz, R.; Elwing, J.; Hill, N.; Ivy, D.; Klinger, J.; Nathan, S.; Oudiz, R.; Robbins, I.; Schilz, R.; Fortin, T.; Wilt, J.; Yung, D.; Austin, E.; Ahmad, F.; Bhatt, N.; Lahm, T.; Frost, A.; Safdar, Z.; Rehman, Z.; Walter, R.; Torres, F.; Bakshi, S.; Archer, S.; Argula, R.; Barnett, C.; Benza, R.; Desai, A.; Maddipati, V. Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension. Circ. Genom. Precis. Med.,  2021, 14(1), e003155.
 [http://dx.doi.org/10.1161/CIRCGEN.120.003155] [PMID: 33320693]

[145]
Boucherat, O.; Chabot, S.; Antigny, F.; Perros, F.; Provencher, S.; Bonnet, S. Potassium channels in pulmonary arterial hypertension. Eur. Respir. J.,  2015, 46(4), 1167-1177.
 [http://dx.doi.org/10.1183/13993003.00798-2015] [PMID: 26341985]

[146]
Traub, R.G.; Sampson, K.J.; Kass, R.S.; Bohnen, M.S. Potassium channels as therapeutic targets in pulmonary arterial hypertension. Biomolecules,  2022, 12(10), 1341.
 [http://dx.doi.org/10.3390/biom12101341] [PMID: 36291551]

[147]
Archer, S.L.; Wu, X.C.; Thébaud, B.; Nsair, A.; Bonnet, S.; Tyrrell, B.; McMurtry, M.S.; Hashimoto, K.; Harry, G.; Michelakis, E.D. Preferential expression and function of voltage-gated, O2-sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: Ionic diversity in smooth muscle cells. Circ. Res.,  2004, 95(3), 308-318.
 [http://dx.doi.org/10.1161/01.RES.0000137173.42723.fb] [PMID: 15217912]

[148]
Bonnet, S.; Michelakis, E.D.; Porter, C.J.; Navarro, A.M.A.; Thébaud, B.; Bonnet, S.; Haromy, A.; Harry, G.; Moudgil, R.; McMurtry, M.S.; Weir, E.K.; Archer, S.L. An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: Similarities to human pulmonary arterial hypertension. Circulation,  2006, 113(22), 2630-2641.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.105.609008] [PMID: 16735674]

[149]
Moudgil, R.; Michelakis, E.D.; Archer, S.L. The role of k+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension. Microcirculation,  2006, 13(8), 615-632.
 [http://dx.doi.org/10.1080/10739680600930222] [PMID: 17085423]

[150]
Yuan, X.J.; Wang, J.; Juhaszova, M.; Gaine, S.P.; Rubin, L.J. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet,  1998, 351(9104), 726-727.
 [http://dx.doi.org/10.1016/S0140-6736(05)78495-6] [PMID: 9504523]

[151]
Olschewski, A.; Li, Y.; Tang, B.; Hanze, J.; Eul, B.; Bohle, R.M.; Wilhelm, J.; Morty, R.E.; Brau, M.E.; Weir, E.K.; Kwapiszewska, G.; Klepetko, W.; Seeger, W.; Olschewski, H. Impact of TASK-1 in human pulmonary artery smooth muscle cells. Circ. Res.,  2006, 98(8), 1072-1080.
 [http://dx.doi.org/10.1161/01.RES.0000219677.12988.e9] [PMID: 16574908]

[152]
Antigny, F.; Hautefort, A.; Meloche, J.; Ouari, B.M.; Manoury, B.; Martin, R.C.; Péchoux, C.; Potus, F.; Nadeau, V.; Tremblay, E.; Ruffenach, G.; Bourgeois, A.; Dorfmüller, P.; Bonnet, B.S.; Fadel, E.; Ranchoux, B.; Jourdon, P.; Girerd, B.; Montani, D.; Provencher, S.; Bonnet, S.; Simonneau, G.; Humbert, M.; Perros, F. Potassium channel subfamily k member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension. Circulation,  2016, 133(14), 1371-1385.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020951] [PMID: 26912814]

[153]
Olschewski, A.; Veale, E.L.; Nagy, B.M.; Nagaraj, C.; Kwapiszewska, G.; Antigny, F.; Lambert, M.; Humbert, M.; Czirják, G.; Enyedi, P.; Mathie, A. TASK-1 (KCNK3) channels in the lung: From cell biology to clinical implications. Eur. Respir. J.,  2017, 50(5), 1700754.
 [http://dx.doi.org/10.1183/13993003.00754-2017] [PMID: 29122916]

[154]
Bohnen, M.S.; Ma, L.; Zhu, N.; Qi, H.; McClenaghan, C.; Jauregui, G.C.; Dewey, F.E.; Overton, J.D.; Reid, J.G.; Shuldiner, A.R.; Baras, A.; Sampson, K.J.; Bleda, M.; Hadinnapola, C.; Haimel, M.; Bogaard, H.J.; Church, C.; Coghlan, G.; Corris, P.A.; Eyries, M.; Gibbs, J.S.R.; Girerd, B.; Houweling, A.C.; Humbert, M.; Guignabert, C.; Kiely, D.G.; Lawrie, A.; MacKenzie Ross, R.V.; Martin, J.M.; Montani, D.; Peacock, A.J.; Pepke-Zaba, J.; Soubrier, F.; Suntharalingam, J.; Toshner, M.; Treacy, C.M.; Trembath, R.C.; Noordegraaf, V.A.; Wharton, J.; Wilkins, M.R.; Wort, S.J.; Yates, K.; Gräf, S.; Morrell, N.W.; Krishnan, U.; Rosenzweig, E.B.; Shen, Y.; Nichols, C.G.; Kass, R.S.; Chung, W.K. Loss-of-function ABCC8 mutations in pulmonary arterial hypertension. Circ. Genom. Precis. Med.,  2018, 11(10), e002087.
 [http://dx.doi.org/10.1161/CIRCGEN.118.002087] [PMID: 30354297]

[155]
McClenaghan, C.; Woo, K.V.; Nichols, C.G. Pulmonary hypertension and ATP-sensitive potassium channels. Hypertension,  2019, 74(1), 14-22.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.12992] [PMID: 31132951]

[156]
Cheron, C.; McBride, S.A.; Antigny, F.; Girerd, B.; Chouchana, M.; Chaumais, M.C.; Jaïs, X.; Bertoletti, L.; Sitbon, O.; Weatherald, J.; Humbert, M.; Montani, D. Sex and gender in pulmonary arterial hypertension. Eur. Respir. Rev.,  2021, 30(162), 200330.
 [http://dx.doi.org/10.1183/16000617.0330-2020] [PMID: 34750113]

[157]
Hester, J.; Ventetuolo, C.; Lahm, T. Sex, gender, and sex hormones in pulmonary hypertension and right ventricular failure. Compr. Physiol.,  2019, 10(1), 125-170.
 [http://dx.doi.org/10.1002/cphy.c190011] [PMID: 31853950]

[158]
Tofovic, S.P. Estrogens and development of pulmonary hypertension: Interaction of estradiol metabolism and pulmonary vascular disease. J. Cardiovasc. Pharmacol.,  2010, 56(6), 696-708.
 [http://dx.doi.org/10.1097/FJC.0b013e3181f9ea8d] [PMID: 20881610]

[159]
Fessel, J.P.; Chen, X.; Frump, A.; Gladson, S.; Blackwell, T.; Kang, C.; Johnson, J.; Loyd, J.E.; Hemnes, A.; Austin, E.; West, J. Interaction between bone morphogenetic protein receptor type 2 and estrogenic compounds in pulmonary arterial hypertension. Pulm. Circ.,  2013, 3(3), 564-577.
 [http://dx.doi.org/10.1086/674312] [PMID: 24618541]

[160]
Denver, N.; Homer, N.Z.M.; Andrew, R.; Harvey, K.Y.; Morrell, N.; Austin, E.D.; MacLean, M.R. Estrogen metabolites in a small cohort of patients with idiopathic pulmonary arterial hypertension. Pulm. Circ.,  2020, 10(1), 1-5.
 [http://dx.doi.org/10.1177/2045894020908783] [PMID: 32206305]

[161]
Ventetuolo, C.E.; Baird, G.L.; Barr, R.G.; Bluemke, D.A.; Fritz, J.S.; Hill, N.S.; Klinger, J.R.; Lima, J.A.C.; Ouyang, P.; Palevsky, H.I.; Palmisciano, A.J.; Krishnan, I.; Pinder, D.; Preston, I.R.; Roberts, K.E.; Kawut, S.M. Higher estradiol and lower dehydroepiandrosterone-sulfate levels are associated with pulmonary arterial hypertension in men. Am. J. Respir. Crit. Care Med.,  2016, 193(10), 1168-1175.
 [http://dx.doi.org/10.1164/rccm.201509-1785OC] [PMID: 26651504]

[162]
Kawut, S.M.; Lima, J.A.C.; Barr, R.G.; Chahal, H.; Jain, A.; Tandri, H.; Praestgaard, A.; Bagiella, E.; Kizer, J.R.; Johnson, W.C.; Kronmal, R.A.; Bluemke, D.A. Sex and race differences in right ventricular structure and function: the multi-ethnic study of atherosclerosis-right ventricle study. Circulation,  2011, 123(22), 2542-2551.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.110.985515] [PMID: 21646505]

[163]
Tello, K.; Richter, M.J.; Yogeswaran, A.; Ghofrani, H.A.; Naeije, R.; Vanderpool, R.; Gall, H.; Tedford, R.J.; Seeger, W.; Lahm, T. Sex differences in right ventricular–pulmonary arterial coupling in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2020, 202(7), 1042-1046.
 [http://dx.doi.org/10.1164/rccm.202003-0807LE] [PMID: 32501730]

[164]
Jacobs, W.; van de Veerdonk, M.C.; Trip, P.; de Man, F.; Heymans, M.W.; Marcus, J.T.; Kawut, S.M.; Bogaard, H.J.; Boonstra, A.; Noordegraaf, V.A. The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest,  2014, 145(6), 1230-1236.
 [http://dx.doi.org/10.1378/chest.13-1291] [PMID: 24306900]

[165]
Liu, A.; Schreier, D.; Tian, L.; Eickhoff, J.C.; Wang, Z.; Hacker, T.A.; Chesler, N.C. Direct and indirect protection of right ventricular function by estrogen in an experimental model of pulmonary arterial hypertension. Am. J. Physiol. Heart Circ. Physiol.,  2014, 307(3), H273-H283.
 [http://dx.doi.org/10.1152/ajpheart.00758.2013] [PMID: 24906919]

[166]
Frump, A.L.; Albrecht, M.; Yakubov, B.; Breuils-Bonnet, S.; Nadeau, V.; Tremblay, E.; Potus, F.; Omura, J.; Cook, T.; Fisher, A.; Rodriguez, B.; Brown, R.D.; Stenmark, K.R.; Rubinstein, C.D.; Krentz, K.; Tabima, D.M.; Li, R.; Sun, X.; Chesler, N.C.; Provencher, S.; Bonnet, S.; Lahm, T. 17β-estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin. J. Clin. Invest.,  2021, 131(6), e129433.
 [http://dx.doi.org/10.1172/JCI129433] [PMID: 33497359]

[167]
Frump, A.L.; Yakubov, B.; Walts, A.; Fisher, A.; Cook, T.; Chesler, N.C.; Lahm, T. Estrogen receptor-α exerts endothelium-protective effects and attenuates pulmonary hypertension. Am. J. Respir. Cell Mol. Biol.,  2023, 68(3), 341-344.
 [http://dx.doi.org/10.1165/rcmb.2022-0224LE] [PMID: 36856412]

[168]
Cunningham, C.M.; Li, M.; Ruffenach, G.; Doshi, M.; Aryan, L.; Hong, J.; Park, J.; Hrncir, H.; Medzikovic, L.; Umar, S.; Arnold, A.P.; Eghbali, M. Y-Chromosome gene, Uty, protects against pulmonary hypertension by reducing proinflammatory chemokines. Am. J. Respir. Crit. Care Med.,  2022, 206(2), 186-196.
 [http://dx.doi.org/10.1164/rccm.202110-2309OC] [PMID: 35504005]

[169]
Liang, S.; Yegambaram, M.; Wang, T.; Wang, J.; Black, S.M.; Tang, H. Mitochondrial metabolism, redox, and calcium homeostasis in pulmonary arterial hypertension. Biomedicines,  2022, 10(2), 341.
 [http://dx.doi.org/10.3390/biomedicines10020341] [PMID: 35203550]

[170]
Xu, W.; Janocha, A.J.; Erzurum, S.C. Metabolism in pulmonary hypertension. Annu. Rev. Physiol.,  2021, 83(1), 551-576.
 [http://dx.doi.org/10.1146/annurev-physiol-031620-123956] [PMID: 33566674]

[171]
Marsboom, G.; Toth, P.T.; Ryan, J.J.; Hong, Z.; Wu, X.; Fang, Y.H.; Thenappan, T.; Piao, L.; Zhang, H.J.; Pogoriler, J.; Chen, Y.; Morrow, E.; Weir, E.K.; Rehman, J.; Archer, S.L. Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ. Res.,  2012, 110(11), 1484-1497.
 [http://dx.doi.org/10.1161/CIRCRESAHA.111.263848] [PMID: 22511751]

[172]
Hong, Z.; Chen, K.H.; DasGupta, A.; Potus, F.; Snary, D.K.; Bonnet, S.; Tian, L.; Fu, J.; Bonnet, B.S.; Provencher, S.; Wu, D.; Mewburn, J.; Ormiston, M.L.; Archer, S.L. MicroRNA-138 and microRNA-25 down-regulate mitochondrial calcium uniporter, causing the pulmonary arterial hypertension cancer phenotype. Am. J. Respir. Crit. Care Med.,  2017, 195(4), 515-529.
 [http://dx.doi.org/10.1164/rccm.201604-0814OC] [PMID: 27648837]

[173]
McMurtry, M.S.; Bonnet, S.; Wu, X.; Dyck, J.R.B.; Haromy, A.; Hashimoto, K.; Michelakis, E.D. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ. Res.,  2004, 95(8), 830-840.
 [http://dx.doi.org/10.1161/01.RES.0000145360.16770.9f] [PMID: 15375007]

[174]
Michelakis, E.D.; McMurtry, M.S.; Wu, X.C.; Dyck, J.R.B.; Moudgil, R.; Hopkins, T.A.; Lopaschuk, G.D.; Puttagunta, L.; Waite, R.; Archer, S.L. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation,  2002, 105(2), 244-250.
 [http://dx.doi.org/10.1161/hc0202.101974] [PMID: 11790708]

[175]
Michelakis, E.D.; Gurtu, V.; Webster, L.; Barnes, G.; Watson, G.; Howard, L.; Cupitt, J.; Paterson, I.; Thompson, R.B.; Chow, K.; O’Regan, D.P.; Zhao, L.; Wharton, J.; Kiely, D.G.; Kinnaird, A.; Boukouris, A.E.; White, C.; Nagendran, J.; Freed, D.H.; Wort, S.J.; Gibbs, J.S.R.; Wilkins, M.R. Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients. Sci. Transl. Med.,  2017, 9(413), eaao4583.
 [http://dx.doi.org/10.1126/scitranslmed.aao4583] [PMID: 29070699]

[176]
Archer, S.L.; Gomberg-Maitland, M.; Maitland, M.L.; Rich, S.; Garcia, J.G.N.; Weir, E.K. Mitochondrial metabolism, redox signaling, and fusion: A mitochondria-ROS-HIF-1α-Kv1.5 O 2 -sensing pathway at the intersection of pulmonary hypertension and cancer. Am. J. Physiol. Heart Circ. Physiol.,  2008, 294(2), H570-H578.
 [http://dx.doi.org/10.1152/ajpheart.01324.2007] [PMID: 18083891]

[177]
Fijalkowska, I.; Xu, W.; Comhair, S.A.A.; Janocha, A.J.; Mavrakis, L.A.; Krishnamachary, B.; Zhen, L.; Mao, T.; Richter, A.; Erzurum, S.C.; Tuder, R.M. Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am. J. Pathol.,  2010, 176(3), 1130-1138.
 [http://dx.doi.org/10.2353/ajpath.2010.090832] [PMID: 20110409]

[178]
Tang, H.; Wu, K.; Wang, J.; Vinjamuri, S.; Gu, Y.; Song, S.; Wang, Z.; Zhang, Q.; Balistrieri, A.; Ayon, R.J.; Rischard, F.; Vanderpool, R.; Chen, J.; Zhou, G.; Desai, A.A.; Black, S.M.; Garcia, J.G.N.; Yuan, J.X.J.; Makino, A. Pathogenic role of mTORC1 and mTORC2 in pulmonary hypertension. JACC Basic Transl. Sci.,  2018, 3(6), 744-762.
 [http://dx.doi.org/10.1016/j.jacbts.2018.08.009] [PMID: 30623134]

[179]
Chettimada, S.; Gupte, R.; Rawat, D.; Gebb, S.A.; McMurtry, I.F.; Gupte, S.A. Hypoxia-induced glucose-6-phosphate dehydrogenase overexpression and -activation in pulmonary artery smooth muscle cells: implication in pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2015, 308(3), L287-L300.
 [http://dx.doi.org/10.1152/ajplung.00229.2014] [PMID: 25480333]

[180]
Zhao, Y.; Peng, J.; Lu, C.; Hsin, M.; Mura, M.; Wu, L.; Chu, L.; Zamel, R.; Machuca, T.; Waddell, T.; Liu, M.; Keshavjee, S.; Granton, J.; de Perrot, M. Metabolomic heterogeneity of pulmonary arterial hypertension. PLoS One,  2014, 9(2), e88727.
 [http://dx.doi.org/10.1371/journal.pone.0088727] [PMID: 24533144]

[181]
Xu, W.; Comhair, S.A.A.; Chen, R.; Hu, B.; Hou, Y.; Zhou, Y.; Mavrakis, L.A.; Janocha, A.J.; Li, L.; Zhang, D.; Willard, B.B.; Asosingh, K.; Cheng, F.; Erzurum, S.C. Integrative proteomics and phosphoproteomics in pulmonary arterial hypertension. Sci. Rep.,  2019, 9(1), 18623.
 [http://dx.doi.org/10.1038/s41598-019-55053-6] [PMID: 31819116]

[182]
Iqbal, M.; Cawthon, D.; Wideman, R.F., Jr; Bottje, W.G. Lung mitochondrial dysfunction in pulmonary hypertension syndrome. II. Oxidative stress and inability to improve function with repeated additions of adenosine diphosphate. Poult. Sci.,  2001, 80(5), 656-665.
 [http://dx.doi.org/10.1093/ps/80.5.656] [PMID: 11372718]

[183]
Masri, F.A.; Comhair, S.A.A.; Dostanic-Larson, I.; Kaneko, F.T.; Dweik, R.A.; Arroliga, A.C.; Erzurum, S.C. Deficiency of lung antioxidants in idiopathic pulmonary arterial hypertension. Clin. Transl. Sci.,  2008, 1(2), 99-106.
 [http://dx.doi.org/10.1111/j.1752-8062.2008.00035.x] [PMID: 20443830]

[184]
Zamanian, R.T.; Hansmann, G.; Snook, S.; Lilienfeld, D.; Rappaport, K.M.; Reaven, G.M.; Rabinovitch, M.; Doyle, R.L. Insulin resistance in pulmonary arterial hypertension. Eur. Respir. J.,  2008, 33(2), 318-324.
 [http://dx.doi.org/10.1183/09031936.00000508] [PMID: 19047320]

[185]
Hansmann, G.; Wagner, R.A.; Schellong, S.; de Perez, J.V.A.; Urashima, T.; Wang, L.; Sheikh, A.Y.; Suen, R.S.; Stewart, D.J.; Rabinovitch, M. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation,  2007, 115(10), 1275-1284.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.106.663120] [PMID: 17339547]

[186]
West, J.; Niswender, K.D.; Johnson, J.A.; Pugh, M.E.; Gleaves, L.; Fessel, J.P.; Hemnes, A.R. A potential role for insulin resistance in experimental pulmonary hypertension. Eur. Respir. J.,  2013, 41(4), 861-871.
 [http://dx.doi.org/10.1183/09031936.00030312] [PMID: 22936709]

[187]
Pugh, M.E.; Robbins, I.M.; Rice, T.W.; West, J.; Newman, J.H.; Hemnes, A.R. Unrecognized glucose intolerance is common in pulmonary arterial hypertension. J. Heart Lung Transplant.,  2011, 30(8), 904-911.
 [http://dx.doi.org/10.1016/j.healun.2011.02.016] [PMID: 21493097]

[188]
Hemnes, A.R.; Luther, J.M.; Rhodes, C.J.; Burgess, J.P.; Carlson, J.; Fan, R.; Fessel, J.P.; Fortune, N.; Gerszten, R.E.; Halliday, S.J.; Hekmat, R.; Howard, L.; Newman, J.H.; Niswender, K.D.; Pugh, M.E.; Robbins, I.M.; Sheng, Q.; Shibao, C.A.; Shyr, Y.; Sumner, S.; Talati, M.; Wharton, J.; Wilkins, M.R.; Ye, F.; Yu, C.; West, J.; Brittain, E.L. Human PAH is characterized by a pattern of lipid-related insulin resistance. JCI Insight,  2019, 4(1), e123611.
 [http://dx.doi.org/10.1172/jci.insight.123611] [PMID: 30626738]

[189]
Tonelli, A.R.; Aytekin, M.; Feldstein, A.E.; Dweik, R.A. Leptin levels predict survival in pulmonary arterial hypertension. Pulm. Circ.,  2012, 2(2), 214-219.
 [http://dx.doi.org/10.4103/2045-8932.97607] [PMID: 22837862]

[190]
Brittain, E.L.; Niswender, K.; Agrawal, V.; Chen, X.; Fan, R.; Pugh, M.E.; Rice, T.W.; Robbins, I.M.; Song, H.; Thompson, C.; Ye, F.; Yu, C.; Zhu, H.; West, J.; Newman, J.H.; Hemnes, A.R. Mechanistic phase II clinical trial of metformin in pulmonary arterial hypertension. J. Am. Heart Assoc.,  2020, 9(22), e018349.
 [http://dx.doi.org/10.1161/JAHA.120.018349] [PMID: 33167773]

[191]
Cheng, X.; Wang, Y.; Du, L. Epigenetic modulation in the initiation and progression of pulmonary hypertension. Hypertension,  2019, 74(4), 733-739.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13458] [PMID: 31476913]

[192]
Archer, S.L.; Marsboom, G.; Kim, G.H.; Zhang, H.J.; Toth, P.T.; Svensson, E.C.; Dyck, J.R.B.; Maitland, M.G.; Thébaud, B.; Husain, A.N.; Cipriani, N.; Rehman, J. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: A basis for excessive cell proliferation and a new therapeutic target. Circulation,  2010, 121(24), 2661-2671.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.109.916098] [PMID: 20529999]

[193]
Meloche, J.; Potus, F.; Vaillancourt, M.; Bourgeois, A.; Johnson, I.; Deschamps, L.; Chabot, S.; Ruffenach, G.; Henry, S.; Breuils-Bonnet, S.; Tremblay, È.; Nadeau, V.; Lambert, C.; Paradis, R.; Provencher, S.; Bonnet, S. Bromodomain-containing protein 4. Circ. Res.,  2015, 117(6), 525-535.
 [http://dx.doi.org/10.1161/CIRCRESAHA.115.307004] [PMID: 26224795]

[194]
Van der Feen, D.E.; Kurakula, K.; Tremblay, E.; Boucherat, O.; Bossers, G.P.L.; Szulcek, R.; Bourgeois, A.; Lampron, M.C.; Habbout, K.; Martineau, S.; Paulin, R.; Kulikowski, E.; Jahagirdar, R.; Schalij, I.; Bogaard, H.J.; Bartelds, B.; Provencher, S.; Berger, R.M.F.; Bonnet, S.; Goumans, M.J. Multicenter preclinical validation of BET inhibition for the treatment of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2019, 200(7), 910-920.
 [http://dx.doi.org/10.1164/rccm.201812-2275OC] [PMID: 31042405]

[195]
Rothman, A.M.K.; Arnold, N.D.; Pickworth, J.A.; Iremonger, J.; Ciuclan, L.; Allen, R.M.H.; Guth-Gundel, S.; Southwood, M.; Morrell, N.W.; Thomas, M.; Francis, S.E.; Rowlands, D.J.; Lawrie, A. MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. J. Clin. Invest.,  2016, 126(7), 2495-2508.
 [http://dx.doi.org/10.1172/JCI83361] [PMID: 27214554]

[196]
Drake, K.M.; Zygmunt, D.; Mavrakis, L.; Harbor, P.; Wang, L.; Comhair, S.A.; Erzurum, S.C.; Aldred, M.A. Altered MicroRNA processing in heritable pulmonary arterial hypertension: An important role for Smad-8. Am. J. Respir. Crit. Care Med.,  2011, 184(12), 1400-1408.
 [http://dx.doi.org/10.1164/rccm.201106-1130OC] [PMID: 21920918]

[197]
Bockmeyer, C.L.; Maegel, L.; Janciauskiene, S.; Rische, J.; Lehmann, U.; Maus, U.A.; Nickel, N.; Haverich, A.; Hoeper, M.M.; Golpon, H.A.; Kreipe, H.; Laenger, F.; Jonigk, D. Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression. J. Heart Lung Transplant.,  2012, 31(7), 764-772.
 [http://dx.doi.org/10.1016/j.healun.2012.03.010] [PMID: 22534459]

[198]
Yang, S.; Banerjee, S.; Freitas, A.; Cui, H.; Xie, N.; Abraham, E.; Liu, G. miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2012, 302(6), L521-L529.
 [http://dx.doi.org/10.1152/ajplung.00316.2011] [PMID: 22227207]

[199]
Pullamsetti, S.S.; Doebele, C.; Fischer, A.; Savai, R.; Kojonazarov, B.; Dahal, B.K.; Ghofrani, H.A.; Weissmann, N.; Grimminger, F.; Bonauer, A.; Seeger, W.; Zeiher, A.M.; Dimmeler, S.; Schermuly, R.T. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am. J. Respir. Crit. Care Med.,  2012, 185(4), 409-419.
 [http://dx.doi.org/10.1164/rccm.201106-1093OC] [PMID: 22161164]

[200]
Shimoda, L.A. Cellular pathways promoting pulmonary vascular remodeling by hypoxia. Physiology,  2020, 35(4), 222-233.
 [http://dx.doi.org/10.1152/physiol.00039.2019] [PMID: 32490752]

[201]
Anderson, L.; Lowery, J.W.; Frank, D.B.; Novitskaya, T.; Jones, M.; Mortlock, D.P.; Chandler, R.L.; de Caestecker, M.P. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol.,  2010, 298(3), R833-R842.
 [http://dx.doi.org/10.1152/ajpregu.00534.2009] [PMID: 20042692]

[202]
Nave, A.H.; Mižíková, I.; Niess, G.; Steenbock, H.; Reichenberger, F.; Talavera, M.L.; Veit, F.; Herold, S.; Mayer, K.; Vadász, I.; Weissmann, N.; Seeger, W.; Brinckmann, J.; Morty, R.E. Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension. Arterioscler. Thromb. Vasc. Biol.,  2014, 34(7), 1446-1458.
 [http://dx.doi.org/10.1161/ATVBAHA.114.303534] [PMID: 24833797]

[203]
Toby, I.T.; Chicoine, L.G.; Cui, H.; Chen, B.; Nelin, L.D. Hypoxia-induced proliferation of human pulmonary microvascular endothelial cells depends on epidermal growth factor receptor tyrosine kinase activation. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2010, 298(4), L600-L606.
 [http://dx.doi.org/10.1152/ajplung.00122.2009] [PMID: 20139181]

[204]
Wang, J.; Weigand, L.; Lu, W.; Sylvester, J.T.; Semenza, G.L.; Shimoda, L.A. Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells. Circ. Res.,  2006, 98(12), 1528-1537.
 [http://dx.doi.org/10.1161/01.RES.0000227551.68124.98] [PMID: 16709899]

[205]
Bonnet, S.; Rochefort, G.; Sutendra, G.; Archer, S.L.; Haromy, A.; Webster, L.; Hashimoto, K.; Bonnet, S.N.; Michelakis, E.D. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc. Natl. Acad. Sci.,  2007, 104(27), 11418-11423.
 [http://dx.doi.org/10.1073/pnas.0610467104] [PMID: 17596340]

[206]
Hlavaty, A.; Roustit, M.; Montani, D.; Chaumais, M.C.; Guignabert, C.; Humbert, M.; Cracowski, J.L.; Khouri, C. Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis. Br. J. Clin. Pharmacol.,  2022, 88(12), 5227-5237.
 [http://dx.doi.org/10.1111/bcp.15436] [PMID: 35679331]

[207]
Abenhaim, L.; Moride, Y.; Brenot, F.; Rich, S.; Benichou, J.; Kurz, X.; Higenbottam, T.; Oakley, C.; Wouters, E.; Aubier, M.; Simonneau, G.; Bégaud, B. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N. Engl. J. Med.,  1996, 335(9), 609-616.
 [http://dx.doi.org/10.1056/NEJM199608293350901] [PMID: 8692238]

[208]
Eddahibi, S.; Adnot, S. Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: lessons for the future in pathogenesis. Respir. Res.,  2002, 3(1), 9.
 [http://dx.doi.org/10.1186/rr181] [PMID: 11806844]

[209]
Eddahibi, S.; Raffestin, B.; Hamon, M.; Adnot, S. Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension? J. Lab. Clin. Med.,  2002, 139(4), 194-201.
 [http://dx.doi.org/10.1067/mlc.2002.122181] [PMID: 12024106]

[210]
Cogolludo, A.; Moreno, L.; Lodi, F.; Frazziano, G.; Cobeño, L.; Tamargo, J.; Perez-Vizcaino, F. Serotonin inhibits voltage-gated K+ currents in pulmonary artery smooth muscle cells: role of 5-HT2A receptors, caveolin-1, and KV1.5 channel internalization. Circ. Res.,  2006, 98(7), 931-938.
 [http://dx.doi.org/10.1161/01.RES.0000216858.04599.e1] [PMID: 16527989]

[211]
Ramirez, R.L., III; Perez, V.D.J.; Zamanian, R.T. Methamphetamine and the risk of pulmonary arterial hypertension. Curr. Opin. Pulm. Med.,  2018, 24(5), 416-424.
 [http://dx.doi.org/10.1097/MCP.0000000000000513] [PMID: 30036313]

[212]
Chen, P.I.; Cao, A.; Miyagawa, K.; Tojais, N.F.; Hennigs, J.K.; Li, C.G.; Sweeney, N.M.; Inglis, A.S.; Wang, L.; Li, D.; Ye, M.; Feldman, B.J.; Rabinovitch, M. Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension. JCI Insight,  2017, 2(2), e90427.
 [http://dx.doi.org/10.1172/jci.insight.90427] [PMID: 28138562]

[213]
Dhalla, I.A.; Juurlink, D.N.; Gomes, T.; Granton, J.T.; Zheng, H.; Mamdani, M.M. Selective serotonin reuptake inhibitors and pulmonary arterial hypertension: A case-control study. Chest,  2012, 141(2), 348-353.
 [http://dx.doi.org/10.1378/chest.11-0426] [PMID: 21852294]

[214]
Chambers, C.D.; Hernandez-Diaz, S.; Van Marter, L.J.; Werler, M.M.; Louik, C.; Jones, K.L.; Mitchell, A.A. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N. Engl. J. Med.,  2006, 354(6), 579-587.
 [http://dx.doi.org/10.1056/NEJMoa052744] [PMID: 16467545]

[215]
Shah, N.P.; Wallis, N.; Farber, H.W.; Mauro, M.J.; Wolf, R.A.; Mattei, D.; Guha, M.; Rea, D.; Peacock, A. Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am. J. Hematol.,  2015, 90(11), 1060-1064.
 [http://dx.doi.org/10.1002/ajh.24174] [PMID: 26284693]

[216]
Ranchoux, B.; Günther, S.; Quarck, R.; Chaumais, M.C.; Dorfmüller, P.; Antigny, F.; Dumas, S.J.; Raymond, N.; Lau, E.; Savale, L.; Jaïs, X.; Sitbon, O.; Simonneau, G.; Stenmark, K.; Cohen-Kaminsky, S.; Humbert, M.; Montani, D.; Perros, F. Chemotherapy-induced pulmonary hypertension: role of alkylating agents. Am. J. Pathol.,  2015, 185(2), 356-371.
 [http://dx.doi.org/10.1016/j.ajpath.2014.10.021] [PMID: 25497573]

[217]
Palasset, T.L.; Chaumais, M.C.; Weatherald, J.; Savale, L.; Jaïs, X.; Price, L.C.; Khouri, C.; Bulifon, S.; Seferian, A.; Jevnikar, M.; Boucly, A.; Manaud, G.; Pancic, S.; Chabanne, C.; Ahmad, K.; Volpato, M.; Favrolt, N.; Guillaumot, A.; Horeau-Langlard, D.; Prévot, G.; Fesler, P.; Bertoletti, L.; Gaubert, R.M.; Lamblin, N.; Launay, D.; Simonneau, G.; Sitbon, O.; Perros, F.; Humbert, M.; Montani, D. Association between leflunomide and pulmonary hypertension. Ann. Am. Thorac. Soc.,  2021, 18(8), 1306-1315.
 [http://dx.doi.org/10.1513/AnnalsATS.202008-913OC] [PMID: 33502958]

[218]
Low, A.T.; Howard, L.; Harrison, C.; Tulloh, R.M.R. Pulmonary arterial hypertension exacerbated by ruxolitinib. Haematologica,  2015, 100(6), e244-e245.
 [http://dx.doi.org/10.3324/haematol.2014.120816] [PMID: 25682609]

[219]
Renard, S.; Borentain, P.; Salaun, E.; Benhaourech, S.; Maille, B.; Darque, A.; Bregigeon, S.; Colson, P.; Laugier, D.; Gaubert, R.M.; Habib, G. Severe pulmonary arterial hypertension in patients treated for hepatitis C with sofosbuvir. Chest,  2016, 149(3), e69-e73.
 [http://dx.doi.org/10.1016/j.chest.2015.09.018] [PMID: 26965976]

[220]
Harper, J.W.; Elledge, S.J. The DNA damage response: ten years after. Mol. Cell,  2007, 28(5), 739-745.
 [http://dx.doi.org/10.1016/j.molcel.2007.11.015] [PMID: 18082599]

[221]
Harrison, J.C.; Haber, J.E. Surviving the breakup: The DNA damage checkpoint. Annu. Rev. Genet.,  2006, 40(1), 209-235.
 [http://dx.doi.org/10.1146/annurev.genet.40.051206.105231] [PMID: 16805667]

[222]
Yeager, M.E.; Halley, G.R.; Golpon, H.A.; Voelkel, N.F.; Tuder, R.M. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ. Res.,  2001, 88(1), E2-E11.
 [http://dx.doi.org/10.1161/01.RES.88.1.e2] [PMID: 11139485]

[223]
Federici, C.; Drake, K.M.; Rigelsky, C.M.; McNelly, L.N.; Meade, S.L.; Comhair, S.A.A.; Erzurum, S.C.; Aldred, M.A. Increased mutagen sensitivity and DNA damage in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2015, 192(2), 219-228.
 [http://dx.doi.org/10.1164/rccm.201411-2128OC] [PMID: 25918951]

[224]
Meloche, J.; Pflieger, A.; Vaillancourt, M.; Paulin, R.; Potus, F.; Zervopoulos, S.; Graydon, C.; Courboulin, A.; Bonnet, B.S.; Tremblay, È.; Couture, C.; Michelakis, E.D.; Provencher, S.; Bonnet, S. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation,  2014, 129(7), 786-797.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.113.006167] [PMID: 24270264]

[225]
Sharma, S.; Aldred, M.A. DNA damage and repair in pulmonary arterial hypertension. Genes,  2020, 11(10), 1224.
 [http://dx.doi.org/10.3390/genes11101224] [PMID: 33086628]

[226]
Li, M.; Vattulainen, S.; Aho, J.; Orcholski, M.; Rojas, V.; Yuan, K.; Helenius, M.; Taimen, P.; Myllykangas, S.; De Perez, J.V.; Koskenvuo, J.W.; Alastalo, T.P. Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am. J. Respir. Cell Mol. Biol.,  2014, 50(6), 1118-1128.
 [http://dx.doi.org/10.1165/rcmb.2013-0349OC] [PMID: 24433082]

[227]
Yakes, F.M.; Van Houten, B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc. Natl. Acad. Sci. USA,  1997, 94(2), 514-519.
 [http://dx.doi.org/10.1073/pnas.94.2.514] [PMID: 9012815]

[228]
Barnes, P.J.; Baker, J.; Donnelly, L.E. Cellular senescence as a mechanism and target in chronic lung diseases. Am. J. Respir. Crit. Care Med.,  2019, 200(5), 556-564.
 [http://dx.doi.org/10.1164/rccm.201810-1975TR] [PMID: 30860857]

[229]
van der Feen, D.E.; Berger, R.M.F.; Bartelds, B. Converging paths of pulmonary arterial hypertension and cellular senescence. Am. J. Respir. Cell Mol. Biol.,  2019, 61(1), 11-20.
 [http://dx.doi.org/10.1165/rcmb.2018-0329TR] [PMID: 30758225]

[230]
Liu, L.; Wei, Y.; Giunta, S.; He, Q.; Xia, S. Potential role of cellular senescence in pulmonary arterial hypertension. Clin. Exp. Pharmacol. Physiol.,  2022, 49(10), 1042-1049.
 [http://dx.doi.org/10.1111/1440-1681.13696] [PMID: 35748218]

[231]
Culley, M.K.; Chan, S.Y. Endothelial senescence: A new age in pulmonary hypertension. Circ. Res.,  2022, 130(6), 928-941.
 [http://dx.doi.org/10.1161/CIRCRESAHA.121.319815] [PMID: 35298304]

[232]
Noureddine, H.; Gary-Bobo, G.; Alifano, M.; Marcos, E.; Saker, M.; Vienney, N.; Amsellem, V.; Maitre, B.; Chaouat, A.; Chouaid, C.; Rande, D.J.L.; Damotte, D.; Adnot, S. Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease. Circ. Res.,  2011, 109(5), 543-553.
 [http://dx.doi.org/10.1161/CIRCRESAHA.111.241299] [PMID: 21719760]

[233]
Culley, M.K.; Zhao, J.; Tai, Y.Y.; Tang, Y.; Perk, D.; Negi, V.; Yu, Q.; Woodcock, C.S.C.; Handen, A.; Speyer, G.; Kim, S.; Lai, Y.C.; Satoh, T.; Watson, A.M.M.; Aaraj, Y.A.; Sembrat, J.; Rojas, M.; Goncharov, D.; Goncharova, E.A.; Khan, O.F.; Anderson, D.G.; Dahlman, J.E.; Gurkar, A.U.; Lafyatis, R.; Fayyaz, A.U.; Redfield, M.M.; Gladwin, M.T.; Rabinovitch, M.; Gu, M.; Bertero, T.; Chan, S.Y. Frataxin deficiency promotes endothelial senescence in pulmonary hypertension. J. Clin. Invest.,  2021, 131(11), e136459.
 [http://dx.doi.org/10.1172/JCI136459] [PMID: 33905372]

[234]
Rai, P.R.; Cool, C.D.; King, J.A.C.; Stevens, T.; Burns, N.; Winn, R.A.; Kasper, M.; Voelkel, N.F. The cancer paradigm of severe pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.,  2008, 178(6), 558-564.
 [http://dx.doi.org/10.1164/rccm.200709-1369PP] [PMID: 18556624]

[235]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell,  2011, 144(5), 646-674.
 [http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]

[236]
van de Veerdonk, M.C.; Marcus, J.T.; Westerhof, N.; de Man, F.S.; Boonstra, A.; Heymans, M.W.; Bogaard, H.J.; Noordegraaf, V.A. Signs of right ventricular deterioration in clinically stable patients with pulmonary arterial hypertension. Chest,  2015, 147(4), 1063-1071.
 [http://dx.doi.org/10.1378/chest.14-0701] [PMID: 25376008]

[237]
van de Veerdonk, M.C.; Kind, T.; Marcus, J.T.; Mauritz, G.J.; Heymans, M.W.; Bogaard, H.J.; Boonstra, A.; Marques, K.M.J.; Westerhof, N.; Vonk-Noordegraaf, A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J. Am. Coll. Cardiol.,  2011, 58(24), 2511-2519.
 [http://dx.doi.org/10.1016/j.jacc.2011.06.068] [PMID: 22133851]

[238]
Claessen, G.; La Gerche, A.; Dymarkowski, S.; Claus, P.; Delcroix, M.; Heidbuchel, H. Pulmonary vascular and right ventricular reserve in patients with normalized resting hemodynamics after pulmonary endarterectomy. J. Am. Heart Assoc.,  2015, 4(3), e001602.
 [http://dx.doi.org/10.1161/JAHA.114.001602] [PMID: 25801760]

[239]
Ritchie, M.; Waggoner, A.D.; Dávila-román, V.G.; Barzilai, B.; Trulock, E.P.; Eisenberg, P.R. Echocardiographic characterization of the improvement in right ventricular function in patients with severe pulmonary hypertension after single-lung transplantation. J. Am. Coll. Cardiol.,  1993, 22(4), 1170-1174.
 [http://dx.doi.org/10.1016/0735-1097(93)90433-2] [PMID: 8409056]

[240]
Schulman, L.L.; Leibowitz, D.W.; Anandarangam, T.; DiTullio, M.R.; McGregor, C.C.; Smith, C.R.; Homma, S. Variability of right ventricular functional recovery after lung transplantation. Transplantation,  1996, 62(5), 622-625.
 [http://dx.doi.org/10.1097/00007890-199609150-00014] [PMID: 8830826]

[241]
Middleton, R.C.; Fournier, M.; Xu, X.; Marbán, E.; Lewis, M.I. Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension. PLoS One,  2017, 12(8), e0183557.
 [http://dx.doi.org/10.1371/journal.pone.0183557] [PMID: 28837618]

[242]
Zhao, Y.D.; Courtman, D.W.; Deng, Y.; Kugathasan, L.; Zhang, Q.; Stewart, D.J. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: Efficacy of combined cell and eNOS gene therapy in established disease. Circ. Res.,  2005, 96(4), 442-450.
 [http://dx.doi.org/10.1161/01.RES.0000157672.70560.7b] [PMID: 15692087]

[243]
Granton, J.; Langleben, D.; Kutryk, M.B.; Camack, N.; Galipeau, J.; Courtman, D.W.; Stewart, D.J. Endothelial NO-synthase gene-enhanced progenitor cell therapy for pulmonary arterial hypertension. Circ. Res.,  2015, 117(7), 645-654.
 [http://dx.doi.org/10.1161/CIRCRESAHA.114.305951] [PMID: 26195220]

[244]
Lewis, M.I. ALPHA Study: Pulmonary ArteriaL Hypertension Treated with CardiosPHere-Derived Allogeneic Stem Cells; American Thoracic Society: Washington D.C, 2023. 

[245]
Middleton, R.S.; Soetkamp, D.; Fournier, M. Mechanisms underlying improvement in right ventricular (RV) function in a rat model of pulmonary arterial hypertension (PAH) and RV dysfunction. Am. J. Respir. Crit. Care Med.,  2021, 203, A3694.
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Current Respiratory Medicine Reviews

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