Interaction between Mas1 and AT1R(A) contributes to enhancement of skeletal muscle angiogenesis by angiotensin-(1-7) in Dahl salt-sensitive rats

The heptapeptide angiotensin-(1–7) (Ang-(1–7)) is protective in the cardiovascular system through its induction of vasodilator production and angiogenesis. Despite acting antagonistically to the effects of elevated, pathophysiological levels of angiotensin II (AngII), recent evidence has identified convergent and beneficial effects of low levels of both Ang-(1–7) and AngII. Previous work identified the AngII receptor type I (AT1R) as a component of the protein complex formed when Ang-(1–7) binds its receptor, Mas1. Importantly, pharmacological blockade of AT1R did not alter the effects of Ang-(1–7). Here, we use a novel mutation of AT1R(A) in the Dahl salt-sensitive (SS) rat to test the hypothesis that interaction between Mas1 and AT1R contributes to proangiogenic Ang-(1–7) signaling. In a model of hind limb angiogenesis induced by electrical stimulation, we find that the restoration of skeletal muscle angiogenesis in SS rats by Ang-(1–7) infusion is impaired in AT1R(A) knockout rats. Enhancement of endothelial cell (EC) tube formation capacity by Ang-(1–7) is similarly blunted in AT1R(A) mutant ECs. Transcriptional changes elicited by Ang-(1–7) in SS rat ECs are altered in AT1R(A) mutant ECs, and tandem mass spectrometry-based proteomics demonstrate that the protein complex formed upon binding of Ang-(1–7) to Mas1 is altered in AT1R(A) mutant ECs. Together, these data support the hypothesis that interaction between AT1R and Mas1 contributes to proangiogenic Ang-(1–7) signaling.