The strategies currently used to halt the development and progression of atherosclerosis and the restenotic neointimal lesions are suboptimal. Understanding the mechanisms of angiogenic growth within the neointima of atherosclerotic and restenotic lesions may lead to the development of new therapies designed to halt the progression of atherosclerosis and inhibit restenosis after percutaneous coronary intervention. Intra-plaque hemorrhage as a result of premature neointimal vasa vasorum represents a critical event in the induction of instability in atherosclerotic coronary lesions. The removal of abnormal neovascularization by molecular therapies may interfere with intra-plaque hemorrhage and hence may halt the progression of atherosclerosis. The growth factors, the angiogenic enzymes, the chemokines, the endothelial specific receptors, and the adhesion molecules, which are involved in the expansion of vasa vasorum, constitute potential targets for such therapies. The vascular endothelial growth factor (VEGF) has an important role in the induction and the maintenance of new blood vessel formation. Thus, the local administration of soluble VEGF receptor, anti-VEGF antibodies, or antibodies that bind to the VEGF receptor, will block VEGF binding to its receptors and thereby block its angiogenic effects. Either stent- or catheterbased therapy may be a viable treatment option for delivering drugs, such as the VEGF-specific antibody (bevacizumab). By inhibiting intralesion angiogenesis, and thus the thickening of neointima, by catheter-based therapy, we may halt the development of high risk unstable plaques and restenosis after coronary interventions. In addition, a combined therapeutic approach with balloon-based strategies with antiangiogenic, antithrombotic, and prohealing agents, and with stents targeting plaques at multiple steps would be more effective.
Antiangiogenesis was proposed as a cancer therapy over 20 years ago and the list of compounds reported to possess antiangiogenic activity is extensive. Inhibitors are grouped as specific and non-specific, depending on whether they inhibit proliferation and/or migration of endothelial cells only or are also cytotoxic for tumor cells. Antiangiogenic therapy is applicable to a wide variety of solid and hematological tumors and there is evidence that tumors do not develop resistance to its effects due to the low mutagenic potential of endothelial cells. It is too early to predict whether antiangiogenesis will be of benefit in hematological malignancies. Strategies that target both the stromal and tumor compartments, such as combining traditional cytotoxic chemotherapy with antiangiogenic agents, may indeed have an impact on drug resistance and improve the therapeutic response. Conventional chemotherapeuticals used at very low doses, strikingly and reversibly impact on certain endothelial cell functions without nonspecific cytotoxic or necrotic damage. The use of low doses in “metronomic” chemotherapy (namely, very frequent or continuous low-dose chemotherapy) as antiangiogenic targeting strategy seem particularly effective against drug-resistant tumors, especially when combined with a secondary antiangiogenic drug. Further studies are needed to secure the comprehensive understanding and to elucidate the molecular basis of the use of these new therapeutic approaches in the treatment of hematological malignancies that actually are suboptimally treated with conventional cytotoxic therapy.