Mechanisms of Angiotensin‐(1‐7) induced MAS1 receptor signaling in the vascular endothelium

Abstract

The renin-angiotensin system (RAS) is important for the regulation of vascular tone and angiogenesis. Angiotensin II (AngII) promotes vasoconstriction, fibrosis, and skeletal muscle angiogenesis through the AT1 receptor. Angiotensin-1-7 (Ang-(1-7)) acts through the Mas1 receptor and is thought to antagonize the AngII-AT1 axis with vasodilation and anti-fibrotic effects. Adding to the RAS complexity, low-dose AngII improves endothelial function and induces vasodilation complementary to Ang-(1-7) during physiologically low levels of AngII. Compared to the AngII-AT1 axis, much less is known about Ang-(1-7) induced Mas1 receptor signaling. Thus, the objective of this study was to define Ang-(1-7) induced Mas1 signaling mechanisms. Here we show Ang-(1-7) stimulation of the Mas1 receptor promotes in vivo vasodilation of the middle cerebral artery, in vivo angiogenesis in skeletal muscle, and in vitro endothelial cell tube formation, all independent of the AngII-AT1 axis. Additionally, using proteomic/genomic strategies we identified Mas1 receptor signaling components related to vasodilation and angiogenesis, including NOS3, NFκB, p38MAPK and ERK1/2. Targeted analysis in the in vivo and in vitro models revealed Ang-(1-7) signaling complementary to the AngII-AT1 axis through p38MAPK and ERK1/2. Our results suggest that despite the antagonistic function of the AT1 and Mas1 receptors under elevated levels of AngII, low-dose AngII and low-dose Ang-(1-7) act synergistically through the MAPK/ERK pathways to induce endothelial dependent angiogenesis and vasodilation.