Angiogenesis, the growth of new capillaries from pre-existing blood vessels, is tightly regulated by a number of vascular growth factors and their cognate receptor tyrosine kinases expressed on endothelial cells; principal among these factors is vascular endothelial growth factor (VEGF). VEGF transduces signals through the enzyme phosphoinositide (PI) 3-kinase, which is a key regulator of endothelial cell growth, migration, and survival. The phospholipid products of PI 3-kinase activate multiple downstream effector proteins, including Akt, to promote the endothelial cellular responses required for angiogenesis. These pathways are disrupted by the lipid phosphatase PTEN, which can inhibit cell growth, migration, and survival. While these effects position PTEN primarily at the plasma membrane, recent data have demonstrated that nuclear PTEN has functions independent of its effects on PI 3-kinase/Akt or its catalytic activity, including interaction with p53 and p300/CBP to regulate p53-mediated transcription. Consistent with these findings, preliminary data from our lab demonstrate that PTEN physically and functionally interacts with hypoxia-inducible factor (HIF)-11, a critical regulator of hypoxic angiogenesis. Specifically, our data presented in this proposal will demonstrate that PTEN and HIF-11 physically interact; that PTEN is both necessary and sufficient for activation of hypoxia-mediated gene expression, a process that is likely HIF-11-dependent; and that PTEN's enhancement of the hypoxic response is independent of its catalytic activity. Our data therefore suggest a key role for PTEN in the regulation of cellular responses to hypoxia, including angiogenesis. Accordingly, we hypothesize that interaction between PTEN and HIF-11 is necessary for HIF-1-mediated gene expression and that endothelial PTEN expression facilitates hypoxic angiogenesis. Secondarily, we hypothesize that PTEN- HIF-11 interaction is required for cell cycle arrest during hypoxia. To further investigate the mechanism and functional consequences of the PTEN-HIF-11 interaction, the Specific Aims of this proposal are to: 1) Determine the mechanisms by which PTEN interacts with HIF-11 and modulates the hypoxic response in cultured endothelial cells in vitro; 2) Determine the effects of PTEN deficiency on hypoxic angiogenesis in murine models of hind limb ischemia and tumor angiogenesis; 3) Determine the effects of endothelium-specific PTEN overexpression on the quiescent adult vasculature and on angiogenesis during hind limb ischemia and tumor growth. Accomplishing these Specific Aims will shed light on the mechanisms by which the PTEN-HIF-11 interaction regulates the response of endothelial cells to hypoxia, including hypoxic angiogenesis in vivo. The results of these studies may lead to the development of novel strategies for the treatment of a variety of angiogenic diseases, including ischemic vascular diseases and cancer. ? ? ? ? ? ? ?
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