Angiotensin II maintains cerebral vascular relaxation via EGF receptor transactivation and ERK1/2

Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1296-303. doi: 10.1152/ajpheart.01325.2008. Epub 2009 Aug 14.

Abstract

This study identified, on the integrative level, two components of the ANG II signaling pathway that lay downstream from the ANG II type 1 (AT(1)) receptor and are critically involved in maintaining vascular relaxation in cerebral resistance arteries. In these experiments, the relaxation of isolated middle cerebral arteries (MCA) in response to ACh (10(-9)-10(-5) M), iloprost (10(-16)-10(-11) g/ml), and reduced PO(2) was lost and the ratio of phospho-ERK/ERK1/2 was significantly reduced in aortas of male Sprague-Dawley rats fed a high-salt (HS; 4% NaCl) diet to suppress plasma ANG II levels. In salt-fed rats, relaxation of MCA in response to these vasodilator stimuli was restored by chronic (3 days) intravenous infusion of either ANG II (5 ngxkg(-1)xmin(-1)) or epidermal growth factor (EGF; 2 microg/h). The protective effect of ANG II infusion to restore vascular relaxation was eliminated by coinfusion of either the EGF receptor kinase inhibitor AG-1478 (20 microg/h), the ERK1/2 inhibitor PD-98059 (10 microg/h), or the protein synthesis inhibitor cycloheximide (5 microg/h). In rats fed a low-salt (0.4% NaCl) diet, MCA relaxation in response to ACh, reduced PO(2), and iloprost was eliminated by intravenous infusion of AG-1478, PD-98059, or cycloheximide. In ANG II-infused rats fed HS diet, and in rats fed LS diet, vasodilator responses to reduced PO(2) and iloprost were unaffected by the p38 MAP kinase inhibitor SB-203580 and the phosphatidylinositol 3-kinase inhibitor wortmannin. These findings indicate that maintenance of normal vascular relaxation mechanisms by ANG II in rat MCA requires activation of the EGF receptor kinase and ERK1/2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin II / administration & dosage
  • Angiotensin II / metabolism*
  • Animals
  • Blood Pressure
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Epidermal Growth Factor / administration & dosage
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Hypertension / enzymology*
  • Hypertension / etiology
  • Hypertension / physiopathology
  • Infusions, Intravenous
  • Male
  • Middle Cerebral Artery / drug effects
  • Middle Cerebral Artery / metabolism*
  • Middle Cerebral Artery / physiopathology
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Synthesis Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Cross-Talk
  • Receptor, Angiotensin, Type 1 / metabolism
  • Signal Transduction
  • Sodium Chloride, Dietary
  • Vasodilation* / drug effects
  • Vasodilator Agents / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Protein Synthesis Inhibitors
  • Receptor, Angiotensin, Type 1
  • Sodium Chloride, Dietary
  • Vasodilator Agents
  • Angiotensin II
  • Epidermal Growth Factor
  • Egfr protein, rat
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3