Determinants of Sinusoidal Endothelial Cell Phenotype.

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DESCRIPTION (provided by applicant): Capillarization is the loss of the highly differentiated sinusoidal endothelial cell (SEC) phenotype with loss of fenestration, thickening of the SEC, and formation of an organized basement membrane. Studies to-date suggest that capillarization is permissive for fibrosis and that understanding capillarization may therefore be crucial for understanding the development of fibrosis. The objective of the current proposal is to further delineate normal regulation of the sinusoidal endothelial cell phenotype and then determine the changes in these regulatory pathways that lead to capillarization. Two of the changes that lead to capillarization are decreased protein expression of vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2. Specific Aim I examines whether the decreased protein expression of VEGF and VEGF receptors is due to decreased gene expression and, if so, whether exogenous hepatocyte growth factor (HGF) normalizes VEGF and VEGF receptor expression in capillarization. Specific Aim II examines whether there is decreased activation of HGF in capillarization, examines the pathways of HGF activation and how the activation pathways are altered in capillarization. Specific Aim III will attempt to develop a workable model of reversal of capillarization and examines the changes that occur during reversal of capillarization. Specific Aim IV examines how nitric oxide maintains SEC phenotype. PUBLIC HEALTH RELEVANCE: The final common pathway leading to morbidity and mortality from most liver diseases is the development of fibrosis, cirrhosis and its complications, and then either liver failure or liver cancer. This project examines the mechanisms that lead to capillarization, a change within the liver microcirculation that is permissive for fibrosis. Improved understanding of this largely unexplored area may lead to strategies to prevent fibrosis.