verbatim): An increase in skeletal muscle mass is accompanied by the proliferation of endothelial cells and growth of arterioles. This vessel growth is triggered by the production of endothelial cell trophic factors by differentiating myofibers, such as vascular endothelial growth factor (VEGF), leading to the induction of angiogenesis. Recent data in cell culture systems demonstrate that Akt signaling is both essential and sufficient for endothelial cell survival, NO production and migration in response to angiogenic growth factor stimulation. Since these cellular responses are believed to be features of the angiogenic process, Akt may be uniquely situated within the endothelial cell signaling cascade to function as a key regulator of blood vessel growth. The experiments proposed here will extend the in vitro observations by testing the role of Akt signaling in blood vessel growth and vascular homeostasis in animal models. The proposed gene transfer studies will provide a better understanding of the signaling pathways that mediate angiogenesis within skeletal muscle and may lead to the development of new molecular therapeutic strategies to control blood vessel growth. Therefore, we propose to: 1) Assess the role of Akt signaling in vascular permeability using the Miles assay, 2) Examine the role of Akt signaling on blood vessel formation in matrigel plugs in mice, 3) Assess the consequences of enhanced endothelial cell Akt signaling in transgenic mice, and 4) Determine the role of endothelial Akt signaling in the revascularization of skeletal muscle in ischemic rabbit hindlimb.
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