title: Angiotensin II maintains cerebral vascular relaxation via EGF receptor transactivation and ERK1/2.
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.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Scott T
authors.initials: ST
authors.lastname: McEwen
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Balus
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Durand
authors.forename: Julian H
authors.initials: JH
authors.lastname: Lombard
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006973:Hypertension / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D044140:Receptor, Angiotensin, Type 1; D017673:Sodium Chloride, Dietary; D014665:Vasodilator Agents; D000804:Angiotensin II; D004815:Epidermal Growth Factor; C483803:Egfr protein, rat; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
references.citation: Hypertension. 1990 Jun;15(6 Pt 2):900-3
references.pmid: 2351440
references.citation: Am J Physiol Heart Circ Physiol. 2004 Oct;287(4):H1590-8
references.pmid: 15155260
references.citation: Am J Physiol. 1992 Sep;263(3 Pt 2):H664-7
references.pmid: 1415589
references.citation: Stroke. 2004 Jul;35(7):1543-7
references.pmid: 15143292
references.citation: Am J Physiol. 1994 Aug;267(2 Pt 2):H580-6
references.pmid: 8067414
references.citation: Arch Intern Med. 2001 Feb 26;161(4):505-6
references.pmid: 11252107
references.citation: Nature. 1999 Jun 10;399(6736):597-601
references.pmid: 10376602
references.citation: Stroke. 2000 Oct;31(10):2487-93
references.pmid: 11022083
references.citation: Am J Hypertens. 1999 Jul;12(7):705-15
references.pmid: 10411368
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H114-20
references.pmid: 16461372
references.citation: Circ Res. 2004 Nov 12;95(10):989-97
references.pmid: 15486316
references.citation: Eur J Pharmacol. 1999 Jul 2;376(1-2):203-6
references.pmid: 10440105
references.citation: FASEB J. 2003 Apr;17(6):770-2
references.pmid: 12586744
references.citation: Am J Physiol Heart Circ Physiol. 2001 May;280(5):H2196-202
references.pmid: 11299222
references.citation: J Pharmacol Exp Ther. 1998 Sep;286(3):1431-8
references.pmid: 9732408
references.citation: AMA Arch Intern Med. 1954 Oct;94(4):525-31
references.pmid: 13196737
references.citation: Hypertension. 2001 Feb;37(2 Pt 2):429-32
references.pmid: 11230313
references.citation: Am J Hypertens. 2000 Apr;13(4 Pt 1):389-95
references.pmid: 10821341
references.citation: Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H929-38
references.pmid: 16603691
references.citation: Am J Physiol Regul Integr Comp Physiol. 2001 Sep;281(3):R878-86
references.pmid: 11507004
references.citation: Curr Opin Cardiol. 2007 Jul;22(4):311-5
references.pmid: 17556883
references.citation: Am J Physiol. 1999 Mar;276(3):H976-83
references.pmid: 10070082
references.citation: Arterioscler Thromb Vasc Biol. 2008 Jan;28(1):61-7
references.pmid: 17962624
references.citation: BMJ. 2007 Apr 28;334(7599):885-8
references.pmid: 17449506
references.citation: Am J Physiol Heart Circ Physiol. 2004 Aug;287(2):H545-52
references.pmid: 15044197
references.citation: Am J Physiol. 1997 Aug;273(2 Pt 2):H869-77
references.pmid: 9277505
references.citation: Am J Physiol. 1994 Aug;267(2 Pt 2):H706-15
references.pmid: 8067426
references.citation: Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1124-33
references.pmid: 12456391
references.citation: Arch Intern Med. 2001 Feb 26;161(4):507-10
references.pmid: 11252108
references.citation: Am J Physiol Heart Circ Physiol. 2002 Jan;282(1):H237-43
references.pmid: 11748068
references.citation: J Cardiovasc Pharmacol. 2005 Nov;46(5):706-12
references.pmid: 16220079
references.citation: Am J Physiol Heart Circ Physiol. 2000 Feb;278(2):H500-6
references.pmid: 10666081
references.citation: J Vasc Res. 2007;44(5):382-90
references.pmid: 17510561
references.citation: Am J Physiol Cell Physiol. 2002 Aug;283(2):C446-55
references.pmid: 12107054
references.citation: Am J Physiol. 1993 Jun;264(6 Pt 2):H1810-6
references.pmid: 8322909
references.citation: Hypertension. 2006 Apr;47(4):699-705
references.pmid: 16505207
references.citation: J Hypertens. 2007 Feb;25(2):361-6
references.pmid: 17211242
references.citation: Microcirculation. 2009 Apr;16(3):220-34
references.pmid: 19235625
references.citation: J Hypertens. 2001 Jul;19(7):1245-54
references.pmid: 11446714
references.citation: J Hypertens. 2002 Apr;20(4):555-9
references.pmid: 11910279
references.citation: Prog Cardiovasc Dis. 2006 Sep-Oct;49(2):59-75
references.pmid: 17046432
references.citation: Hypertension. 1988 Aug;12(2):96-101
references.pmid: 3410531
references.citation: Am J Physiol Heart Circ Physiol. 2000 Jul;279(1):H7-H14
references.pmid: 10899036