This application is focused on the role of endothelial cell survival pathways via Akt/PKB activation in developmental angiogenesis. In previous studies, we have elucidated factors that activate survival pathways at multiple stages of vascular development. In particular, we highlighted the role of VEGF-A in providing survival remodeling retinal and tumor blood vessels. Based on preliminary data and published studies, we put forth the hypothesis that survival signals determine vascular morphogenesis first by stabilizing vascular assembly, and later by governing remodeling. The processes of sprouting and vessel assembly determine where blood vessels will form, and remodeling determines the final architecture. Remodeling is the differentiation process that transitions the immature vascular plexus (typified by the early yolk sac and early retinal vasculature) into a fully mature organ consisting of perivascular support cells and highly ordered and heterogeneous network of arterial and venous vessels of appropriate sizes and shapes. Soluble factors (such as VEGF-A) are required for the immature blood vessels to survive until pericyte investment occurs. To test this overall hypothesis, we have designed two aims to address the following related topics: the first is centered on the controls of endothelial Akt survival signaling to the earliest phases of blood vessel development, i.e. vessel assembly and sprouting. The second is focused on the ability of constitutively active Akt to control normal developmental microvascular remodeling. Thus, at cellular and molecular levels, we propose to explore the complex process of endothelial cell survival signaling that governs vascular morphogenesis during normal development. ? ?
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