In adult tissues, vascular homeostasis is maintained by a quiescent endothelium with minimal proliferative activity, minimal adhesion for circulating leukocytes and platelets, and a relatively tight barrier for regulation of fluid balance. It is generally believed that outside-in signaling through the endothelial cell-cell and cell-matrix adhesions provide key relays of extracellular cues by which the cells respond to, although these precise signaling events remain far from clear. We propose that endothelial p120 catenin (p120ctn), an adherens junction protein bound to VE-cadherin, may play a pivotal role in maintenance of vascular homeostasis through its dual ability to regulate cell-cell adhesion by controlling VE-cadherin turnover as well as relay signaling into the nucleus. At present, neither the physiological nor pathological roles of p120ctn in endothelial function beyond that of cell cell adhesion have been studied and little information is known. We show preliminary results that loss of endothelial p120ctn expression was a potent stimulus for transcriptional activation of ICAM-1, MMP-13, and MMP-1 promoter reporter genes, as well as transcription factors, NF-?B, AP-1, and Kaiso, and suggest that p120ctn exerts negative regulation of gene transcription. Recent advances in understanding the biology of p120ctn indicated that p120ctn may accomplish this regulation through functions distinct from that for cell-cell adhesion; specifically, p120ctn can be a direct transcription cofactor (such as for Kaiso), a direct regulator of Rho proteins, or indirectly by controlling the sequestration of a- and ?-catenins on cadherin. In this application, we propose to investigate the physiological significance of the decreased p120ctn expression in the lung vascular endothelium, specifically, whether the decrease could lead to loss of vascular endothelial homeostasis. We will also begin to explore the involvement of Rho and MAPK as a potential relay pathway for p120ctn to exert negative transcription regulation. The following two aims will test the guiding hypothesis that decreased (or dysfunctional) p120ctn induces an endothelial phenotype with loss of quiescence (i.e., proliferative) and increased inflammatory potential (i.e., adhesion for circulating leukocytes) through signaling into the nucleus and regulate transcription of critical genes. Specific Aim 1 will test the hypothesis that loss of p120ctn expression signals to the nucleus to activate transcription of genes for endothelial cell proliferation and pro-inflammatory activities. Specific Aim 2 will investigate whether loss of p120ctn induces endothelial proliferation and pro-inflammatory activities in cultured endothelial cells and the in vivo mouse lung endothelium. PUBLIC HEALTH RELEVANCE. Impaired function of the endothelial cells that line blood vessels are recognized as key contributing elements, and possibly causative factors, to many diseases, such as acute lung injury, pulmonary hypertension, atherosclerosis, diabetes, and cancer. In this proposal, we seek to better understand how a healthy vasculature is controlled in tissues, which is vital to better design treatments to prevent or reverse pathological disease processes. [unreadable] [unreadable] [unreadable]