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

Scott T. McEwen, Sarah F. Balus, Matthew J. Durand, Julian H. Lombard

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 (AT1) 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 PO2 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 ng·kg-1·min-1) or epidermal growth factor (EGF; 2 μg/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 μg/h), the ERK1/2 inhibitor PD-98059 (10 μg/h), or the protein synthesis inhibitor cycloheximide (5 μg/h). In rats fed a low-salt (0.4% NaCl) diet, MCA relaxation in response to ACh, reduced PO2, 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 PO2 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.

Original languageEnglish (US)
Pages (from-to)H1296-H1303
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number4
DOIs
StatePublished - Oct 2009
Externally publishedYes

Keywords

  • Cell signaling
  • Epidermal growth factor
  • Extracellular signal-regulated kinase
  • Hypertension
  • Oxidative stress
  • Renin-angiotensin system
  • Salt

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