Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

Abstract

Objective Angiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1 (AT1R). Angiotensin 1-7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, while the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7). Approach and Results This study shows that low dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similarly to a low, subpressor dose of AngII acting through AT1R. Additionally, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Utilizing proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho Family GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen activated protein kinase (MAPK), and extracellular signal-related kinase (ERK) signaling. Further experimental antagonism of ERK1/2 and p38MAPK signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7). Conclusions These results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII as compared to the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AT1R signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of MAPK/ERK signaling in maintaining vascular function.

Interaction between Mas1 and AT1RA contributes to enhancement of skeletal muscle angiogenesis by angiotensin-(1-7) in Dahl salt-sensitive rats

“…For instance, Ang-(1-7) contributes to endothelial homeostasis via ERK1/2, eNOS, PI3-kinase and Akt, all of which are also associated with AngII signaling via AT1R [4,[8][9][10]. A few relatively detailed proteomic analyses of Ang-(1-7)/Mas signaling have been performed in our laboratory and by others, and the results of those studies further support a convergence in AngII/AT1R and Ang-(1-7)/Mas signaling [3,11].…”

“…However, recent studies reaffirm that AngII/AT1R signaling plays a key role in vascular homeostasis. For instance, renin suppression in animal models impairs angiogenesis [1] and vascular reactivity to vasodilator stimuli [2], and restoration of physiological AngII levels in models of impaired renin regulation restores vascular reactivity and endothelial function [3,4].…”

“…Conversely, 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].…”

Epidemiological analysis of the early 38 fatalities in Hubei, China, of the coronavirus disease 2019

“…Among the death cases, persons with hypertension and /or diabetes made up the largest share, which could be explained by the fact that hypertension and diabetes top the chronic disease chart in China [27]. ACE2 is a crucial regulator of the renin-angiotensin system, and plays a regulatory role in the central regulation of blood pressure and cardiovascular function and could become an attractive target for the treatment of hypertension [28,29]. COVID-19 virus uses the receptor ACE2 to enter into target cells [30], precisely the same as SARS-CoV.…”

Molecular Basis of the Brain Renin Angiotensin System in Cardiovascular and Neurologic Disorders: Uncovering a Key Role for the Astroglial Angiotensin Type 1 Receptor AT1R

“…Interestingly, AT1R activity was reduced in the amygdala of mice brains that lacked the MAS receptor, further highlighting the crosstalk among the various components of the RAS (Von Bohlen und Halbach et al, 2000). Interestingly, a subpressor dose of Ang II has a similar angiogenic response to a low dose of Ang (1-7), further highlighting the complex interplay between various components of the RAS (Hoffmann et al, 2017). Although the cannabinoid type 1 receptor has been demonstrated to potentiate AT1R profibrinogenic activity by way of heterodimerization (Rozenfeld et al, 2011), it has also has been demonstrated to diminish AT1R's ability to activate key signaling pathways in astrocytes (Haspula and Clark, 2017b).…”