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Angiotensin‐(1–7) Requires both Mas1 and AT1 Receptors to Restore Angiogenesis

The Renin‐Angiotensin System plays an important role in many physiological processes such as sodium homeostatis, regulating vascular tone and angiogenesis. The octapeptide Angiotensin II (AngII) acting through the AT1 receptor has long been known to promote vasoconstriction, fibrosis, cell proliferation and skeletal muscle angiogenesis in response to exercise or electrical stimulation. A second vasoactive peptide of the Renin‐Angiotensin System, Angiotensin‐1–7 (Ang‐(1–7)), acts through the Mas1 receptor and is generally thought to have many physiological actions that are antagonistic to the actions of the AngII‐AT1 axis, such as vasodilation, anti‐fibrotic and anti‐proliferative effects. We hypothesized Ang‐(1–7) acting through the Mas1 receptor could restore skeletal muscle angiogenesis in response to electrical stimulation. Little is known about the signaling events initiated by Mas1 receptor activation by Ang‐(1–7) relative to AngII‐AT1 activity. Here we show in Sprague Dawley rats with Renin suppressed through high dietary salt intake, which suppresses angiogenesis, that infused Ang‐(1–7) acting through the Mas1 receptor restores angiogenesis in vivo in skeletal muscle in response to electrical stimulation and in vitro in a tube formation assay using rat microvascular endothelial cells, in both cases independent of AngII. Using advanced proteomic methodology to characterize the components of Mas1 receptor signaling we identified signaling pathways that may play a role in the observed angiogenic response, such as nascent protein synthesis, exocytosis, cellular reorganization and regulators such as NO, NF‐kappaB and ERK1/2 signaling. Inhibition of ERK1/2 signaling inhibited tube formation by endothelial cells stimulated by AngII or Ang‐(1–7). We further assessed angiogenesis in response to electrical stimulation promoted by Ang‐(1–7) in SS‐Mas1em1Mcwi (Mas1 mutant knockout) and SS‐Agtr1aem5Mcwi (AT1 mutant knock out) strains, and compared to wild‐type SS/Mcwi. We found reduced angiogenesis to electrical stimulation after Ang‐(1–7) or orally active Ang‐(1–7) analog AVE0991 treatment in both the Mas1 mutant and the AT1 mutant knock outs relative to the SS/Mcwi. The RAS is a complex physiological system that can affect a wide range of processes in the cardiovascular system. Even though the AT1 and Mas1 receptor axes largely have antagonistic functions, we have shown that capillary angiogenesis can both be restored by AngII‐AT1 or Ang‐(1–7)‐Mas1 activity, and the restoration depends on the presence of functioning Mas1 and AT1 receptors.