Angiogenesis in wound healing

During wound healing, angiogenic capillary sprouts invade the fibrin/fibron ectin-rich wound clot and within a few days organize into a microvascular n etwork throughout the granulation tissue. As collagen accumulates in the gr anulation tissue to produce scar, the density of blood vessels diminishes. A dynamic interaction occurs among endothelial cells, angiogenic cytokines, such as FGF, VEGF, TGF-beta, angiopoietin, and mast cell tryptase, and the extracellular matrix (ECM) environment. Specific endothelial cell ECM rece ptors are critical for these morphogenetic changes in blood vessels during wound repair. In particular, alpha nu beta3, the integrin receptor for fibr in and fibronectin, appears to be required for wound angiogenesis: alpha nu beta3 is expressed on the tips of angiogenic capillary sprouts invading th e wound clot, and functional inhibitors of alpha nu beta3 transiently inhib it granulation tissue formation. Recent investigations have shown that the wound ECM can regulate angiogenesis in part by modulating integrin receptor expression. mRNA levels of alpha nu beta3 in human dermal microvascular en dothelial cells either plated on fibronectin or overlaid by fibrin gel were higher than in cells plated on collagen or overlaid by collagen gel. Wound angiogenesis also appears to be regulated by endothelial cell interaction with the specific three-dimensional ECM environment in the wound space. In an in vitro model of human sprout angiogenesis, three-dimensional fibrin ge l, simulating early wound clot, but not collagen gel, simulating late granu lation tissue, supported capillary sprout formation. Understanding the mole cular mechanisms that regulate wound angiogenesis, particularly how ECM mod ulates ECM receptor and angiogenic factor requirements, may provide new app roaches for treating chronic wounds.