Endothelial dysfunction through genetic deletion or inhibition of the G protein-coupled receptor Mas: A new target to improve endothelial function
BACKGROUND: Endothelial dysfunction is an initial step in the pathogenesis of cardiovascular diseases. Since we previously identified the G protein-coupled receptor Mas as a receptor for angiotensin (Ang)-(1-7), a heptapeptide with endothelium-dependent vasorelaxant properties, we investigated whether alterations on the Ang-(1-7)/Mas axis alter endothelial function. RESULTS: Ang-(1-7)-mediated relaxation of murine wild-type mesenteric arteries was equally impaired in both wild-type arteries pretreated with the Ang-(1-7) receptor blocker, A779, and arteries isolated from Mas-deficient mice. Importantly, the response to the endothelium-dependent vasorelaxant, bradykinin (BK), and acetylcholine (ACh) effects were comparably inhibited, while endothelium-independent vessel relaxation by sodium nitroprusside was unaltered in these vessels. Hypothesizing endothelial dysfunction, we proved the in-vivo relevance of the ex-vivo findings investigating mesenteric properties after 1 week of minipump infusion of A779 in wild-type mice. Both BK- and ACh-induced relaxation were significantly impaired in wild-type vessels of pretreated animals. A779-induced impairment of endothelial function was confirmed in vitro, since BK-mediated nitric oxide (NO) release was increased by Ang-(1-7) and blunted by A779 pretreatment in primary human endothelial cell cultures. CONCLUSIONS: Our data highlight a pivotal role for the receptor Mas in preserving normal vascular relaxation. Consequently, Mas agonists arise as a promising tool in the treatment of cardiovascular diseases characterized by endothelial dysfunction.
|Keywords||Angiotensin-(1-7), Endothelial dysfunction, Mas receptor, Nitric oxide|
|Persistent URL||dx.doi.org/10.1097/HJH.0b013e3282f0143c, hdl.handle.net/1765/35889|
Peiró, C, Vallejo, S, Gembardt, F, Azcutia, V, Heringer-Walther, S, Rodríguez-Mañas, L, … Walther, T. (2007). Endothelial dysfunction through genetic deletion or inhibition of the G protein-coupled receptor Mas: A new target to improve endothelial function. Journal of Hypertension, 25(12), 2421–2425. doi:10.1097/HJH.0b013e3282f0143c