Epidermal Growth Factor Receptor Is Critical For Angiotensin II–Mediated Hypertrophy in Cerebral ArteriolesNovelty and Significance
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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.
- Received October 22, 2014.
- Revision received November 3, 2014.
- Accepted February 1, 2015.
- © 2015 American Heart Association, Inc.