ROLES OF CAVEOLIN-1 IN ANGIOTENSIN II-INDUCED HYPERTROPHY AND INWARD REMODELING OF CEREBRAL PIAL ARTERIOLES

Abstract

Angiotensin II (Ang II) is a major determinant of inward remodeling and hypertrophy in pial arterioles that may have an important role in stroke during chronic hypertension. Previously we found that epidermal growth factor receptor (EGFR) is critical in Ang II-mediated hypertrophy that may involve caveolin-1 (Cav-1). In this study, we examined the effects of Cav-1 and matrix metalloproteinase-9 (MMP9) on Ang II-mediated structural changes in pial arterioles. Cav-1-deficient (Cav-1−/−), MMP9-deficient (MMP9−/−) and wild-type (WT) mice were infused with either Ang II (1000 ng/kg/min) or saline via osmotic minipumps for 28 days (n=6–8 per group). Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of pial arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area of the wall was determined histologically in pressurized fixed pial arterioles. Expression of Cav-1, MMP9, phosphorylated-EGFR and Akt was determined by western blotting and immunohistochemistry. Deficiency of Cav-1 or MMP9 did not affect Ang II-induced hypertension. Ang II increased expression of Cav-1, pEGFR and Akt in WT mice that was attenuated in Cav-1−/− mice. Ang II-induced hypertrophy, inward remodeling and increased MMP9 expression in pial arterioles was prevented in Cav-1−/− mice. Ang II-mediated increases in MMP9 expression and inward remodeling, but not hypertrophy, was prevented in MMP9−/− mice. In conclusion, Cav-1 is essential in Ang II-mediated inward remodeling and hypertrophy in pial arterioles. Cav-1 induced MMP9 is exclusively involved in inward remodeling, not hypertrophy. Further studies are needed to determine the role of Akt in Ang II-mediated hypertrophy.