This Article Accepted Manuscript (PDF) All Versions of this Article: 136/1/125    most recent REP-07-0374v1 Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Herr, D. Articles by Wulff, C. Search for Related Content PubMed PubMed Citation Articles by Herr, D. Articles by Wulff, C.

Regulation of endothelial proliferation by the Renin-Angiotensin-System in human umbilical vein endothelial cells

D Herr, Obstetrics/Gynecology, University Hospital Ulm, Ulm, 89075, Germany
M Rodewald, Obstetrics/Gynecology, University Hospital Ulm, 89075, Germany
H Fraser, Reproductive Science, 2Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, Edinburgh, Edinburgh, United Kingdom
G Hack, Obstetrics/Gynecology, University Hospital Ulm, Ulm, Germany
R Konrad, Obstetrics/Gynecology, Ulm, United States
R Kreienberg, Obstetrics/Gynecology, University Hospital Ulm, Ulm, Germany
C Wulff, Obstetrics/Gynecology, University Hospital Ulm, Ulm, Germany

Correspondence: Daniel Herr, Email: daherr{at}gmx.de

Abstract

This study was performed in order to evaluate the role of Angiotensin II in physiological angiogenesis. Human umbilical vein endothelial cells (HUVEC) were stained for Angiotensin II type 1 receptor (At1R) immunocytochemically and for gene expression of Renin-Angiotensin-System (RAS) components. The regulation of the angiogenesis-associated genes VEGF and Angiopoietins (Ang1 and Ang2) were studied using quantitative RT-PCR. Furthermore, we examined the effect of Angiotensin II on the proliferation of HUVEC using ki-67 as well as BrdU immunocytochemistry and investigated whether administration of At1R blocker, candesartan, or VEGF antagonist Flt-1-Fc could suppress the observed Angiotensin II dependent pro-angiogenic effect.

The At1R was expressed in HUVEC and administration of Angiotensin II significantly increased gene expression of VEGF and decreased gene expression of Ang1. Since the expression of Ang2 was not affected significantly the ratio of Ang1/Ang2 was decreased. In addition, significant increased endothelial cell proliferation was observed after stimulation with Angiotensin II, which was suppressed by simultaneous administration of candesartan or VEGF antagonist, Flt-1-Fc.

These results indicate the potential capacity of Angiotensin II to influence angiogenesis by regulation of angiogenesis associated genes via At1R. Since VEGF blockade opposed the effect of Angiotensin II on cell proliferation, it is hypothesised that VEGF mediates the Angiotensin II-dependent effect in concert with changes in angiopoietin expression. This is the first report of the RAS in regulation of angiogenesis associated genes in physiology indicating an involvement of At1R.