In contrast to invertebrate species, in which oxygen can be adequately transported to all cells by diffusion, vertebrates, with their larger body size, require a circulatory system that is specialized for oxygen delivery. When systemic oxygen delivery is inadequate, cardiac output increases and red blood cell production is augmented. However, when oxygen delivery is impaired locally, as in a tissue in which perfusion has been interrupted by injury or vascular stenosis, a primary response is angiogenesis, the sprouting of new blood vessels.

The complex process of angiogenesis (reviewed in refs. 1–3) begins when cells within a tissue respond to hypoxia by increasing their production of VEGF. VEGF is secreted and binds to cognate receptor tyrosine kinases (VEGFR1 and VEGFR2) located on the surface of vascular endothelial cells. Receptor ligation triggers a cascade of intracellular signaling pathways that initiate angiogenesis. The clinical importance of this biological process has become increasingly apparent over the last decade, and angiogenesis now represents a major focus for novel therapeutic approaches to the prevention and treatment of multiple diseases, most notably ischemic cardiovascular disease and cancer (1–3).