This corresponds to 120,000 amputations annually in the United States.1 Leg amputation due to atherosclerotic critical limb ischemia (CLI) gives rise to an acute mortality rate of around 30% and a 5-year survival rate of less than 30%.2, 3 Poor prognosis and the increasing number of patients with CLI have created a growing need for new therapies to induce angiogenesis, with the most emphasis being placed on gene and cell therapy. Therapeutic angiogenesis is the iatrogenic, induced formation of a capillary network in ischemic tissue by altering Inhibitors,research,lifescience,medical the local milieu to provide a proangiogenic environment. Akt inhibitor Physiologically, angiostatic

mediators generally outweigh the angiogenic molecules, preventing the occurrence of angiogenesis. Introduction of a vector to force-express an angiogenic factor disrupts this equilibrium. Inhibitors,research,lifescience,medical Therapeutic angiogenesis can occur via two mechanisms: vasculogenesis and angiogenesis.4 Vasculogenesis is the in situ assembly of precursor cells, or angioblasts, into capillaries, whereas angiogenesis is the formation of new capillaries from Inhibitors,research,lifescience,medical preexisting vessels. Angiogenesis is initiated by vasodilatation and increased permeability of the vessel (Figure 1). The molecular, cellular, humoral, and mechanical factors result in

destabilization of vessel wall homeostasis. This leads to endothelial cell proliferation, migration, and formation of a tube, which then matures with the arrival of pericytes and smooth muscle cells. Numerous soluble growth factors and inhibitors, cytokines and proteases, and

extracellular matrix proteins and adhesion Inhibitors,research,lifescience,medical molecules strictly control this multi-step process. No influx of nontissue resident cells appears to be required.5 The resulting capillaries are small, with a diameter of about 10 to Inhibitors,research,lifescience,medical 20 μm, and cannot be considered sufficient to compensate or substitute for a large occluded transport artery. Originally, vasculogenesis and angiogenesis were considered independent events, with vasculogenesis occurring exclusively during embryogenesis and angiogenesis occurring in adults. It is now recognized that both mechanisms are involved in vessel formation within to a single microenvironment.6, 7 Vasculogenesis has been reported to contribute between 3.5–25% to adult neovascularization.7 Figure 1 Biology of Angiogenesis.32Panel A. Angiogenic sprouting. (A) Sprouting is controlled by the balance between pro-angiogenic signals (+), such as vascular endothelial growth factor (VEGF), and factors that promote quiescence (–), such as tight pericyte … Distinct from angiogenesis or vasculogenesis, arteriogenesis may be the mechanism with the greatest clinical importance. Arteriogenesis is also known as collateralization.