Role of epidermal growth factor receptor on angiotensin II‐induced hypertrophy and remodeling in cerebral arterioles

Abstract

We examined the effect of epidermal growth factor receptor (EGF‐R) inhibition on structural alternation in cerebral arterioles induced by angiotensin II (Ang II). C57BL/6J mice (8–10 weeks old) were infused with Ang II (1000 ng/kg/day) via osmotic minipumps for 28 days. AG1478 (12 mg/kg), a specific EGF‐R tyrosine kinase inhibitor, was given intraperitoneally once a day. Systolic arterial pressure (SAP) was measured by a tail‐cuff method. At the end of the treatment, pressure and diameter of cerebral arterioles were measured through an open cranial window in anesthetized mice. Chronic infusion of Ang II increased SAP (139±7 vs control of 115±5 mmHg), reduced external diameter of maximally dilated (by EDTA) cerebral arterioles (ED, 56±6 vs 66±3 μm at 50 mmHg intravascular pressure), and increased vessel wall cross sectional area (CSA, 527±31 vs 356±49 μm2) and immunohistochemical staining density of EGF‐R (19±2 vs 1±1 %). Thus, Ang II raised blood pressure, transactivated EGF‐R, promoted hypertrophy and remodeling. Concurrent treatment of AG1478 with Ang II did not attenuate increases in SAP (140±2 mmHg) or remodeling (ED: 57±3 μm), but prevented hypertrophy (CSA: 352±19 μm2) and diminished EGF‐R staining density (9±1 %). These findings suggest that increased activity of EGF‐R via transactivation by Ang II type 1 receptors may play an important role in Ang II‐induced hypertrophy, but may not in remodeling.