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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/H1296    most recent 01325.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by McEwen, S. T. Articles by Lombard, J. H. PubMed PubMed Citation Articles by McEwen, S. T. Articles by Lombard, J. H.

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

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted December 23, 2008 ; accepted in final form August 3, 2009

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.

hypertension; salt; cell signaling; oxidative stress; renin-angiotensin system; epidermal growth factor; extracellular signal-regulated kinase