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Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium. Arterioscler Thromb Vasc Biol 2017 Mar;37(3):433-445 PMID: 28082260 PMCID: PMC5323371

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 AND RESULTS: 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.

Author List

Hoffmann BR, Stodola TJ, Wagner JR, Didier DN, Exner EC, Lombard JH, Greene AS

Authors

Andrew S. Greene PhD Interim Vice Chair, Chief, Professor in the Biomedical Engineering department at Medical College of Wisconsin
Brian R. Hoffmann PhD Assistant Professor in the Biomedical Engineering department at Medical College of Wisconsin
Julian H. Lombard PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin I
Angiotensin II
Angiotensin II Type 1 Receptor Blockers
Animals
Dose-Response Relationship, Drug
Electric Stimulation
Endothelial Cells
Endothelium, Vascular
Extracellular Signal-Regulated MAP Kinases
Gene Expression Regulation
Male
Middle Cerebral Artery
Neovascularization, Physiologic
Peptide Fragments
Proto-Oncogene Proteins
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1
Receptors, G-Protein-Coupled
Signal Transduction
Vasodilation
p38 Mitogen-Activated Protein Kinases



View this publication's entry at the Pubmed website PMID: 28082260
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