Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium.
Arterioscler Thromb Vasc Biol
; 37(3): 433-445, 2017 Mar.
Article
em En
| MEDLINE
| ID: mdl-28082260
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. Angiotensin 1 to 7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, whereas 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 ANDRESULTS:
This study shows that low-dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similar to a low, subpressor dose of AngII acting through AngII receptor type 1. In addition, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Using proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho family of GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen-activated protein kinase, and extracellular signal-related kinase signaling. Further experimental antagonism of extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinase 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 compared with the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AngII receptor type 1 signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of mitogen-activated protein kinase/extracellular signal-related kinase signaling in maintaining vascular function.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Vasodilatação
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Endotélio Vascular
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Transdução de Sinais
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Proteínas Proto-Oncogênicas
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Neovascularização Fisiológica
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Artéria Cerebral Média
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Células Endoteliais
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Receptores Acoplados a Proteínas G
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article