Mechanisms of ocular angiogenesis and its molecular mediators

Angiogenesis is defined as the formation of new blood vessels from the existing vasculature. It is a highly coordinated process occurring during development of the retinal vasculature, ocular wound healing, and in pathological conditions. Complex interactions are involved between non-vascular and microvascular cells, such as endothelial cells and pericytes, via several angiogenic growth factors and inhibitors. Of these growth factors, vascular endothelial growth factor (VEGF) has emerged as the single most important causal agent of angiogenesis in health and disease in the eye. During the angiogenic process, endothelial cells shift from a homogeneous quiescent population into a population of heterogeneous phenotypes, each with a distinct cellular fate. So far, three angiogenic specialized phenotypes have been identified: (1) 'tip cells', which pick up guidance signals and migrate through the extracellular matrix; (2) 'stalk cells', which proliferate, form junctions, produce extracellular matrix, and form a lumen, and (3) 'phalanx cells', which do not proliferate, but align and form a smooth monolayer. Eventually, a robust mature new blood vessel is formed which is capable of supplying blood and oxygen to tissues. Pathological angiogenesis is a key component of several irreversible causes of blindness. In most of these conditions, angiogenesis is part of a wound healing response culminating, via an angiofibrotic switch, in fibrosis and scar formation which leads to blindness. Currently, VEGF-A antagonists are standard care in the treatment of exudative age-related macular degeneration, and have been found to be a valuable additional treatment strategy in several other vascular retinal diseases.