McEwen ST, Balus SF, Durand MJ, Lombard JH
Angiotensin II Maintains Cerebral Vascular Relaxation via EGF Receptor Trans-Activation and ERK 1/2. [JOURNAL ARTICLE]
Am J Physiol Heart Circ Physiol 2009 Aug 14.
This study identified on the integrative level two components of the angiotensin II (ANG II) signaling pathway that lie downstream from the 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 acetylcholine (ACh; 10(-9)-10(-5) M), iloprost (10(-16)-10(-11) g/mL), and reduced PO2 were lost and the ratio of phospho-ERK/ERK 1/2 was significantly reduced in aortas of male Sprague-Dawley rats fed 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) i.v. infusion of either ANG II (5 ng/kg/min) or EGF (2 microg/hr). The protective effect of ANG II infusion to restore vascular relaxation was eliminated by co-infusion of either the epidermal growth factor (EGF) receptor kinase inhibitor AG1478 (20 microg/hr), the extracellular-signal regulated kinase (ERK) 1/2 inhibitor PD98059 (10 microg/hr); or the protein synthesis inhibitor cycloheximide (5 microg/hr). In rats fed low salt (0.4% NaCl) diet, MCA relaxation in response to ACh, reduced PO2 and iloprost were eliminated by i.v. infusion of AG1478, PD98059, 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 SB203580 and the PI3 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 ERK 1/2. Key words: Hypertension, Salt, Cell Signaling, Angiotensin II.
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