Abstract 262: Drebrin Regulates Aortic Remodeling in Angiotensin II-Induced Hypertension

Abstract

The actin-binding protein, Drebrin, is upregulated in response to arterial injury and reduces smooth muscle cell migration/proliferation through its interaction with the actin cytoskeleton. Because hypertensive aortic remodeling involves smooth muscle cell (SMC) activation and synthesis of extracellular matrix, we tested the hypothesis that Drebrin inhibits this process. To determine the effect of Drebrin deficiency in SMCs on hypertensive aortic remodeling, we induced hypertension by implanting osmotic mini-pumps to infuse angiotensin II (Ang II, 1000 ng/kg/min) or vehicle (0.9% NaCl) continuously for 28 days in SM22-α Cre +/- ; Dbn flox/flox mice (SMC- Dbn -/- mice) and controls. Blood pressure (BP) responses to Ang II treatment were assessed by telemetry. After completion of Ang II infusion, the degree of aortic remodeling was assessed by computerized tomography of histologic cross-sections of the proximal ascending aorta. Despite observing no difference in the extent of Ang II-induced hypertension in SMC- Dbn -/- mice compared with controls, SMC- Dbn -/- mice exhibited a significant increase in medial hypertrophy and outward remodeling. Wall thickness/body weight was increased by 61 ± 2% (p<0.01) in SMC- Dbn -/- mice compared with controls, and lumen area/body weight was increased by 102 ± 9% (p<0.01). Cellular proliferation and matrix deposition were increased in the proximal aortas of Ang II-treated SMC- Dbn -/- mice compared with controls as evidenced by increased immunoreactivity for PCNA, p-ERK, and Collagen I. SMC loss of Drebrin also resulted in increased Ang II-induced pro-inflammatory signaling as evidenced by increased expression of VCAM-1, p-P65 and MMP-9 and increased CD68 positive cellular proliferation in response to chronic Ang II infusion. We conclude that SMC loss of Drebrin augments adverse aortic remodeling in angiotensin II-induced hypertension.