Epidermal growth factor receptor is critical for angiotensin II-mediated hypertrophy in cerebral arterioles.
Angiotensin II (Ang II) is a major determinant of vascular remodeling in the cerebral circulation during chronic hypertension, which is an important risk factor for stroke. We examined the molecular mechanism of Ang II-mediated cerebrovascular remodeling that involves the epidermal growth factor receptor (EGFR) pathway. Mutant EGFR mice (waved-2), their heterozygous control (wild-type [WT]), and C57BL/6J mice were infused with Ang II (1000 ng kg(-1) min(-1)) or saline via osmotic minipumps for 28 days (n=8 per group). Eight of the Ang II-infused C57BL/6J mice were cotreated with AG1478 (12 mg/kg per day, IP), a specific EGFR tyrosine kinase inhibitor. Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of cerebral arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area of the wall was determined in pressurized fixed cerebral arterioles. Expression of phosphorylated EGFR (p-EGFR), caveolin-1 (Cav-1), and c-Src was determined by western blotting and immunohistochemistry. Mutation of EGFR or AG1478 treatment did not affect Ang II-induced hypertension. Ang II increased the expression of p-EGFR in WT mice, confirming the activation of EGFR. Ang II induced hypertrophy and inward remodeling of cerebral arterioles in WT mice. Hypertrophy, but not remodeling, was prevented in waved-2 and AG1478-treated C57BL/6J mice. Ang II increased p-EGFR, Cav-1, and c-Src expression in WT but not in waved-2 or AG1478-treated C57BL/6J mice. These results suggest that Ang II-induced hypertrophy in cerebral arterioles involves EGFR-dependent signaling and may include Cav-1 and nonreceptor tyrosine kinase c-Src. This signaling pathway seems to be limited to Ang II-induced hypertrophy, but not inward remodeling, and is independent of blood pressure.
From the Department of Pathology, University of Iowa College of Medicine, Iowa City.
Siu-Lung
SL
Chan
From the Department of Pathology, University of Iowa College of Medicine, Iowa City.
Shaikamjad
S
Umesalma
From the Department of Pathology, University of Iowa College of Medicine, Iowa City. g-baumbach@uiowa.edu.
Gary L
GL
Baumbach
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects*; D002536:Cerebral Arteries / Q000378:metabolism / Q000473:pathology*; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D012313:RNA / Q000235:genetics; D015398:Signal Transduction; D066253:Vascular Remodeling
D000804:Angiotensin II; D012313:RNA; D066246:ErbB Receptors
angiotensin II; hypertrophy; mice; vascular remodeling