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
Date
08/18/2009Pubmed ID
19684181Pubmed Central ID
PMC2770770DOI
10.1152/ajpheart.01325.2008Scopus ID
2-s2.0-70349631795 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
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.
Author List
McEwen ST, Balus SF, Durand MJ, Lombard JHAuthor
Matt Durand PhD Associate Professor in the Physical Medicine and Rehabilitation department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Angiotensin IIAnimals
Blood Pressure
Disease Models, Animal
Dose-Response Relationship, Drug
Epidermal Growth Factor
ErbB Receptors
Hypertension
Infusions, Intravenous
Male
Middle Cerebral Artery
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Phosphorylation
Protein Kinase Inhibitors
Protein Synthesis Inhibitors
Rats
Rats, Sprague-Dawley
Receptor Cross-Talk
Receptor, Angiotensin, Type 1
Signal Transduction
Sodium Chloride, Dietary
Vasodilation
Vasodilator Agents
