A vigorous angiogenic response is a conspicuous component of normal wound repair. Within healing wounds angiogenesis proceeds until vessel density is nearly three times that of uninjured tissue. During the resolution phase of wound repair, many newly formed capillaries regress, resulting in a residual vessel density similar to normal uninjured skin. In the proliferative phase, vascular endothelial cell growth factor (VEGF), a potent proangiogenic factor, stimulates wound angiogenesis through the binding of its receptors VEGFR2 and neuropilin-1, which are expressed on the developing vasculature. Interestingly, wound keratinocytes also express VEGF receptors, although keratinocytes express only the VEGFR1 variant. While many details of the proangiogenic phase in wounds are known, a notable gap in our knowledge surrounds the events contributing to vessel regression. VEGF levels decline just prior to vessel regression, yet vascular regression seems to be mechanistically more complex than a simple withdrawal of stimulus.
The specific aims of this application are: 1) To identify the function of the VEGF receptors expressed by wound keratinocytes, 2) To determine whether the simple loss of VEGF is responsible for vascular regression, 3) To establish the role ofpericytes in protecting wound capillaries from vascular regression, and 4) To examine the role of collagen remodeling in vascular regression.
In Aim 1, the function of VEGFR1 found on wound keratinocytes will be determined by specific antibody neutralization of the receptor.
Aim 2 will utilize a sponge wound model to produce a continuous high level of VEGF. The ability of this manipulation to overcome vascular regression will be determined.
Aim 3 will examine the role of pericytes, cells that surround mature capillaries, in providing a survival advantage to wound capillaries.
Aim 4 will determine the influence of collagen remodeling on vascular regression. The long-term objective of this research is to fully understand the process of wound angiogenesis both in normal and poorly healing wounds. This research will improve our understanding of wound angiogenesis, including the distinctive regression phase that is unique to physiologic angiogenesis. The results will contribute to our capability to generate rationale therapeutics for poorly healing wounds.
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