Abstract 1042: BNP Promotes Angiogenesis by VEGF Production via JAK2/STAT3 and ERK Signaling Pathway in Human Endothelial Cells
B-type natriuretic peptide (BNP) released predominantly from cardiac ventricles is indicated to exert direct actions on vascular cells via natriuretic peptide receptor-A (NPR-A). In this study, we examined effects of BNP signaling on endothelia cells. In human coronary artery endothelial cells and umbilical vein endothelial cells, we detected NPR-A expression, which was significantly abolished by depletion of NPR-A by RNA interference. Recombinant human BNP induced tyrosine phosphprylation of JAK2, which led to STAT3 and ERK phosphorylation. Depletion of NPR-A inhibited JAK2, STAT3 and ERK phosphorylation which was induced by BNP. BNP also increased cyclic guanosine-monophosphate (cGMP) levels, which was decreased by depletion of NPR-A by RNA interference. The cGMP agonist 8-Br-cGMP activated tyrosine and serine phosphorylation of STAT3 in endothelial cells. Pretreatment with specific inhibitors of cGMP-activated protein kinase (PKG), Rp-8-Br-cGMP, BNP-induced tyrosine and serine phosphorylation was inhibited. BNP dose-dependently decreased in the expression of a cyclin-dependent protein kinase inhibitor p21Cip1, but not of p27Kip1, which were abolished by pretreatment with p44/42 inhibitor PD98059, or the depletion of NPR-A and STAT3 by RNA interference. BNP promoted angiogenesis, cell proliferation, viability and migration, which was reversed by pretreatment with PD98059, or the depletion of STAT3 and NPR-A by RNA interference. Furthermore, BNP dose-dependently promoted VEGF mRNA production, which was decreased by pretreatment with PD98059, or the depletion of STAT3 and NPR-A by RNA interference. These results indicate that BNP activated JAK2, STAT3, and ERK phosphorylation, as well as elevated c-GMP levels which led to STAT3 phosphorylation through NPR-A. BNP may promote angiogenesis by VEGF production and attenuating cell cycle via JAK2, ERK and STAT3 signaling pathway in endothelial cells.