Clinician guide to angiogenesis.

Case Presentation: J.A. is a 63year-old man with type II diabetes and hypercholesterolemia. He has suffered 2 previous myocardial infarctions and has chronic angina. Previous angiography showed diffuse 3-vessel coronary artery disease not amenable to conventional revascularization. What are the current concepts surrounding the use of therapeutic coronary angiogenesis in this setting? Since recognition of the central role of angiogenic factors in tumor growth over 30 years ago,1 physiological and pathological angiogenesis has been implicated in diverse conditions, including vascular insufficiency, inflammation, and diabetic retinopathy. Despite considerable advances in medical therapy and improvements in revascularization procedures for coronary artery disease, a substantial proportion of patients suffer from refractory angina or recurrent myocardial ischemia requiring hospitalization. In the past decade, a number of clinical trials have examined the role of therapeutic angiogenesis for myocardial ischemia. In this article, we focus on the fundamental mechanisms of angiogenesis and discuss current and future issues in therapeutic coronary angiogenesis. Principles of Angiogenesis Three distinct mechanisms of new blood vessel formation have been identified: Vasculogenesis, angiogenesis, and arteriogenesis. Vasculogenesis refers to the formation of blood vessels from endothelial progenitor cells, a process that was initially described as occurring during embryonic development, and more recently, in adult animals.2 Angiogenesis involves the sprouting of new capillaries from preexisting vessels, whereas arteriogenesis refers to remodeling of newly formed or preexisting vascular channels into larger and well-muscularized arterioles and collateral vessels.3 The generation of new vascular channels by angiogenesis and arteriogenesis has been shown in both animal models of myocardial ischemia and in patients with coronary disease.4 Importantly, the formation of collateral vessels in acute and chronic coronary occlusion may preserve perfusion to ischemic myocardium and thereby maintain myocardial function. Angiogenesis is a dynamic process of endothelial proliferation and differentiation. The formation of a functioning vasculature requires the orchestrated interaction of endothelial cells, extracellular matrix, and surrounding cells. The major physiological stimuli for angiogenesis include tissue ischemia and hypoxia, inflammation, and shear stress. A number of specific factors are known to stimulate or inhibit angiogenesis, including vascular growth factors, inflammatory cytokines, adhesion molecules, and nitric oxide. Importantly, regulation of these factors in both spatial and temporal domains is critical to efficient neovascularization, and different biological activities are required in the different phases of angiogenesis from initiation to maturation (Figure).