The extracellular matrix (ECM) is composed of fiber proteins (collagen,
elastin, and fibrillin), specialized proteins (fibronectin and laminin), and ground
substances such as glycosaminoglycan (GAG) and proteoglycan (PG). PGs are
complexes of core proteins and GAG. GAGs such as heparin-like substances, except
hyaluronic acid, are abundantly sulfated and interact with arginine-rich motifs including
the heparin-binding domains (HBD) of cytokines, chemokines, and growth factors. The
existence of an optimal dose is expected for the cardiovascular effects of erythropoietin
(EPO)-derivatives. Asialoerythropoietin (AEPO), intermediate products of EPO in the
Golgi, as well as the metabolic products of EPO by desialylation are expected to play
roles in tissues as paracrine cytokines that protect organs from damage. Like VEGF,
AEPO expresses tissue affinity, and tissues can maintain a constant concentration of
AEPO. However, AEPO is not suitable for the treatment of anemia or endothelial cells
injury. We have synthesized a chimeric derivative of EPO, heparin-binding
erythropoietin (HEPO), introduced with the HBD of human PLGF-2. HEPO expressed
a long-acting nature in erythropoiesis in vivo as expected. Surprisingly, the natural
recovery of blood flow in a mouse limb ischemia model was inhibited by the
administration of HEPO. PLGF shares the same receptors with VEGF-A, and expresses
stronger angiogenic activity than VEGF-A. HBD of PLGF-2 is richer in arginine and
lysine than VEGF-A. HEPO may inhibit the angiogenic effects of intrinsic VEGF by
occupying tissue GAG with the HBD of PLGF-2.
Keywords: Heparin-binding domain, glycosaminoglycan, paracrine, long-acting
erythropoietin, angiogenesis inhibitor, placental growth factor.
