The healing wound is an excellent model for the study of physiologic angiogenesis and subsequent controlled vascular regression. Within healing wounds, a vigorous initial angiogenic response creates a vessel density nearly twice that of uninjured tissue. As wounds resolve, the newly formed capillaries regress, and vessel density returns to baseline. Previous investigations in our laboratory have documented that the proangiogenic phase in wounds is mediated by the sequential production of two proangiogenic factors, FGF-2 and VEGF. In contrast, capillary regression in wounds is suspected to involve specific, but as yet unidentified, antiangiogenic signals. Compelling new evidence implicates a specific endothelial cell ligand family named the angiopoietins as critical regulators of both capillary growth and regression. The broad long-term objective of this application is to elucidate the mechanism by which capillary growth and regression are modulated in healing wounds.
The specific aims are 1) to understand the regulation of the proangiogenic phase of wound repair, including the modulation of FGF-2 and VEGF levels, 2) to identify the role of the angiopoietins (Ang1 and Ang2) in wound angiogenesis, and 3) to determine if an antiangiogenic environment dictates capillary regression in resolving wounds. Using a murine model of excisional wound healing, the regulation of the production of the angiogenic mediators FGF-2, VEGF, and the angiopoietins will be examined by immunodetection (immunohistochemistry, and ELISA) and molecular biological analyses (Northern analysis and in situ hybridization). To determine the role of these mediators in wound angiogenesis, specific blocking agents for each factor will be administered, and the effect on the wound healing process examined. Finally, changes in the overall angiogenic balance in wounds, from proangiogenic to antiangiogenic, will be assessed with both in vitro (chemotaxis) and in vivo (corneal and matrigel) assays. The results of the proposed studies have implications for abnormal wound healing, as well as pathologic processes that involve disregulated angiogenesis, such as inflammatory diseases and solid tumor growth.
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