title: 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. 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).
  
  
  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.
authors.affiliation: From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Hoffmann
authors.affiliation: From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stodola
authors.affiliation: From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee.
authors.forename: Jordan R
authors.initials: JR
authors.lastname: Wagner
authors.affiliation: From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee.
authors.forename: Daniela N
authors.initials: DN
authors.lastname: Didier
authors.affiliation: From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Exner
authors.affiliation: From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee.
authors.forename: Julian H
authors.initials: JH
authors.lastname: Lombard
authors.affiliation: From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee. agreene@mcw.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greene
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C000715472:Mas1 protein, rat; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D000803:Angiotensin I; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C118790:angiotensin I (1-7)
keywords: angiotensin II; endothelium, vascular; phenotype; renin-angiotensin system; vasodilation