Angiogenesis and arteriogenesis--not yet for prescription.

Angiogenesis is the growth of new vessels from preexisting vessels by sprouting and intussusception with ischemia being the major stimulus. Circulating endothelial precursor cells have recently been found to participate in this process. The remodeling of preexisting bridging collateral arterioles, i.e., arteriogenesis, should be a much more efficient mechanism to compensate for the gradual or intermittent occlusion of a major epicardial or peripheral artery. Arteriogenesis is associated with an active growth process. It is probably not dependent on ischemia but initiated by local hemodynamic and mechanical effects on the vessel that occur with increasing blood flow. A variety of growth factors that act not only by stimulating endothelial and smooth muscle cell proliferation and migration, as well as substances that increase recruitment and activation of monocytes have been demonstrated to stimulate angiogenesis and arteriogenesis. Several clinical phase I trials suggest the feasibility and short-term safety of treatment with growth factors or their genes. The VIVA trial, the only phase II trial that has been published in this field, employed VEGF165 by intracoronary infusion followed by several intravenous infusions and did not demonstrate any increase of exercise time or angina by VEGF over placebo. The strong sustained placebo effect was surprising. Concerns about the long-term exacerbation of angiogenesis-dependent pathologic processes, like malignant tumors, atherosclerotic plaque formation and proliferative retinopathies, will require careful follow-up. Pro-angiogenic and pro-arteriogenic therapies may need further sophistication before they enter clinical practice.