Abstract
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 AT1RA 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 AT1RA knockout rats. Enhancement of endothelial cell (EC) tube formation capacity by Ang-(1-7) is similarly blunted in AT1RA mutant ECs. Transcriptional changes elicited by Ang-(1-7) in SS rat ECs are altered in AT1RA 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 AT1RA mutant ECs. Together, these data support the hypothesis that interaction between AT1R and Mas1 contributes to proangiogenic Ang-(1-7) signaling.
Highlights
Microvascular dysfunction is an important risk factor for highly prevalent cardiovascular diseases including hypertension and diabetes
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 AT1RA knockout rats
Transcriptional changes elicited by Ang-(1–7) in SS rat endothelial cell (EC) are altered in AT1RA 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 AT1RA mutant ECs
Summary
Microvascular dysfunction is an important risk factor for highly prevalent cardiovascular diseases including hypertension and diabetes. Under conditions of RAS suppression (i.e. low-renin hypertension or salt-induced renin-suppression) restoration of physiological AngII levels and low-dose Ang-(1–7) have convergent, beneficial effects such as improvement of endothelial function and rescue of impaired vasodilator responses[3]. The Ang-(1–7)/Mas axis of the RAS is relatively understudied, especially compared to the AngII/AT1R axis, but recent studies have identified several key mediators of Ang-(1–7)/Mas signaling. Several of these pathways are important in AngII/AT1R signaling. We investigate the restoration of normal microvascular function in the Dahl salt-sensitive rat, a genetic model of low renin-angiotensin system activity and impaired angiogenesis, to test the hypothesis that proangiogenic Ang-(1–7) signaling is dependent on the. Using wild type Dahl salt-sensitive (SS-AT1WT) rats and Dahl salt-sensitive rats with a novel mutation in AT1R resulting in an early truncation and loss of function (SS-AT1KO), we assess the consistency of Ang-(1–7) induced effects at the physiological level using a hind-limb model of angiogenesis, at the cellular level via endothelial cell tube formation, and at the molecular level via qPCR and tandem mass spectrometry-based proteomics
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