ANGIOTENSIN II DEPENDENT GENE REGULATION IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS INVOLVES VEGF-SIGNALING AND ANGIOGENESIS

Abstract

The present study examined the effect of angiotensin II on the regulation of different angiogenesis associated genes in human endothelial umbilical vein cells (HUVEC) and investigated whether administration of At1R blocker candesartan could suppress this angiotensin II dependent proangiogenic effect. Angiotensin II dependent expression of different angiogenesis-associated genes was analysed in HUVECs 1) after stimulation with angiotensin II, 2) after blocking of At1R by candesartan and 3) after neutralizing of vascular endothelial growth factor (VEGF) by VEGF trap FLT-Fc. Gene expression of VEGF, Angiopoeitin 1 (Ang1), Angiopoeitin 2 (Ang2), Von-Hippel-Lindau-Tumorsuppressorgene (VHL), tissue inhibitor of matrix metalloproteinases 1 (TIMP-1), and hypoxia inducible transcription factor 2alpha (HIF-2alpha) was investigated using TaqMan Real-Time-PCR. A possible proangiogenic effect of angiotensin II on HUVEC was investigated using ki-67 immunocytofluorescence. VEGF, Ang1, VHL, TIMP-1, HIF-2alpha and the At1R were expressed in HUVEC. Angiotensin II significantly increased gene expression of VEGF and VHL and decreased gene expression of Ang1. Expression of Ang2, TIMP-1, and HIF-2alpha were not affected significantly. In addition significantly increased endothelial cell proliferation was observed after stimulation with angiotensin II. This was suppressed by simultaneous administration of candesartan or VEGF trap FLT-Fc. It is hypothesized that angiotensin II influences angiogenesis by regulation of angiogenesis associated genes via At1R. Since VEGF inhibition opposed the effect of angiotensin II on cell proliferation, we suggest VEGF acts as a mediator of this angiotensin II-dependent effect. In addition, we hypothesize, that targeting angiogenesis by inhibition of At1R may lead to new therapeutical anti-angiogenic strategies. (poster)