Vascular endothelial cells respond to ischemic stress in tissues by undergoing an angiogenic repair process. We have previously shown that activation of Akt signaling is an important mediator of the angiogenic response in endothelial cells. More recently, we have shown that hypoxia and hypoxic- reoxygenation are powerful stimuli of AMP-activated kinase (AMPK) signaling within endothelial cells, and that AMPK signaling significantly contributes to biological responses in endothelial cells under conditions of ischemic stress including eNOS activation, cellular survival and migration. Based upon these data, it has been proposed that AMPK signaling promotes endothelial cell function and angiogenic responses in ischemic tissues. Recent studies have shown that LKB1 functions as a key regulator of both AMPK and Akt signaling in a number of tissues including liver, skeletal muscle, myocardium and various cancers. However, very little is known about the role of LKB1 in regulating endothelial cell function and angiogenic responses. The proposed research will examine the role of endothelial cell LKB1 in regulating downstream signaling proteins, involving both AMPK and Akt signaling pathways. Related experiments will manipulate the expression of LKB1 and downstream proteins and assess the effects of these perturbations on cellular responses that are associated with angiogenesis, including migration, proliferation, survival and NO production. These observations will be extended in vivo through the construction and characterization of conditional knockout mice that are deficient for LKB1 in the vascular endothelium. LKB1 conditional knockout mice will then be subjected to ischemic surgeries and angiogenic responses will be analyzed. ]n the revised application, new experiments are proposed to examine the upstream regulators of LKB1. Specifically, experiments will focus on the role of the histone deacetvlate SIRT1. To accomplish these goals we will: 1. Dissect signaling pathways that function downstream from LKB1 in endothelial cells that are acutely exposed to ROS. 2. Assess the role of LKB1in regulating endothelial cell responses that contribute to angiogenesis. 3. Construct and characterize mice that are deficient for LKB1 in the vascular endothelium. I 4. Construct and characterize mice that are deficient for SIRT1 in the vascular endothelium.
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