vascular endothelial growth factor receptor-2 couples cyclo-oxygenase-2 with pro-angiogenic actions of leptin on human endothelial cells血管内皮生长因子受体2夫妻cyclo-oxygenase-2 pro-angiogenic瘦素对人类内皮细胞的行为.pdfVIP

Vascular Endothelial Growth Factor Receptor-2 Couples Cyclo-Oxygenase-2 with Pro-Angiogenic Actions of Leptin on Human Endothelial Cells 1 1 2 2 3 Elena Garonna , Kathleen M. Botham , Graeme M. Birdsey , Anna M. Randi , Ruben R. Gonzalez-Perez , Caroline P. D. Wheeler-Jones1* 1 Department of Basic Sciences, Royal Veterinary College, University of London, London, United Kingdom, 2 Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, United Kingdom, 3 Morehouse School of Medicine, Atlanta, Georgia, United States of America Abstract Background: The adipocyte-derived hormone leptin influences the behaviour of a wide range of cell types and is now recognised as a pro-angiogenic and pro-inflammatory factor. In the vasculature, these effects are mediated in part through its direct leptin receptor (ObRb)-driven actions on endothelial cells (ECs) but the mechanisms responsible for these activities have not been established. In this study we sought to more fully define the molecular links between inflammatory and angiogenic responses of leptin-stimulated human ECs. Methodology/Principal Findings: Immunoblotting studies showed that leptin increased cyclo-oxygenase-2 (COX-2) expression (but not COX-1) in cultured human umbilical vein ECs (HUVEC) through pathways that depend upon activation of both p38 mitogen-activated protein kinase (p38MAPK) and Akt, and stimulated rapid phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) on Tyr1175. Phosphorylation of VEGFR2, p38MAPK and Akt, and COX-2 induction in cells challenged with leptin wer