345 Endothelial dysfunction by genetic deletion or inhibition of the G prteoin-coupled receptor Mas — a new target to improve endothelial function

Resumen

Endothelial dysfunction is an initial step in the pathogenesis of cardiovas- cular diseases. We previously identified the G protein-coupled receptor Mas as an endogenous receptor for angiotensin (Ang)-(1-7), a heptapep- fide with endothelium-dependent vasorelaxant properties. We here inves- tigated whether alterations on the Ang-(1-7)/Mas a~xis could have impact on endothelial function. Ang-(1-7)-mediated rela~xation in isolated mesenteric arteries of 3- months old Mas-deficient mice was significantly impaired compared to their matched wildtype controls. This reduction in Ang-(1-7) relaxation was comparable to that in isolated wildtype vessels pretreated by the spe- cific Ang-(1-7) receptor blocker, A779. Furthermore, in Mas-deficient mesenteries, the response to the endothelium-dependent vasorelaxant bradykinin (BK) was reduced and acetylcholine (ACt) effects completely inhibited. Notable, endothelium-independent vessel rela~xafion by sodium nitroprusside (SNP) was not altered in these vessels. To explore in vitro mechanisms of alterations in BK response we investigated nitric oxide (NO) release in cultured bovine and primary human endothelial cells of different vascular beds pretreated by Ang-(1-7) or A779 for 24 or 72 h. A779-pretreatment blunted BK-mediated NO release and decreased endothelial NO synthase quantity. To demonstrate the in vivo relevance of the cell culture findings, mesenteric properties were investigated after one-week minipump infusion of Ang-(1-7) or A779 in wildtype mice. As in Mas-deficient vessels, BK induced rela~xafion was significantly im- paired in wildtype vessels pretreated by A779. Our data implicates generalized endothelial dysfunction in mice lacking the Mas receptor, highlighting on a pivotal role for the receptor in pre- serving normal vascular reactivity. Consequently, Mas agonists arise as a promising tool in the treatment of cardiovascular diseases characterized by endothelial dysfunction.