Abstract P123: Angiotensin Ii Type 1a Receptor Expressed Insmooth Muscle Cells Is Required Forangiotensin Ii-induced Vascular Remodeling But Not For Cardiac Hypertrophy

Abstract

Angiotensin II Type 1a Receptor (AT1a) has been shown to play a critical role in cardiovascular diseases. We have demonstrated that ADAM17 mediates cardiovascular remodeling induced by angiotensin II (AngII) by using an SM22α Cre reporter, which expresses in smooth muscle cells (SMC) and cardiomyocytes. It is conceivable that AT1 signaling in SMC specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis. Deficiency of SMC AT1a receptors via endogenous SM22α promoter knock-in (KISMKO) results in diminished hypertension and cardiac hypertrophy induced by AngII. However, we have limited understanding whether SMC AT1a receptors affect vascular fibrosis and cardiac hypertrophy. Thus, this study was designed to elucidate the roles of the SMC AT1a receptor in cardiovascular remodeling using two distinct SMC AT1a receptor deficient mice. One line is the KISMKO, and another line is Tamoxifen inducible SMMHC-Cre AT1aflox/flox mouse (SMMHCKO) silencing in SMC but not cardiac myocytes. 8 to 12-week-old male mice were infused with AngII (1 μg/kg/min) for 2 weeks. Cardiac hypertrophy was assessed by heart-to-body weight ratios and found to be reduced in KISMKO mice compared with control mice (6.04 mg/g versus 4.89 mg/g, p=0.032), whereas ratios were not altered in SMMHCKO mice (5.31 mg/g versus 5.47 mg/g, p=0.941). Histological assessment demonstrated that perivascular fibrosis in coronary arteries was increased in control mice and attenuated in both KISMKO and SMMHCKO mice (1.27 vs. 0.22, p<0.0001 and 0.70 vs. 0.16, p<0.0001, respectively.). Medial thickness of descending aorta was increased in control mice and these phenotypic changes were attenuated in both KISMKO and SMMHCKO mice (97 vs. 56 μm, p<0.0001 and 98 vs. 74 μm, p<0.0001, respectively.). In conclusion, SMC AT1a receptors could mediate AngII-induced vascular remodeling including perivascular fibrosis but not cardiac hypertrophy. Cardiac myocyte AT1a appears critical for cardiac hypertrophy. Our data together with a past manuscript demonstrate a protective effect of SMC AT1a silencing in overall vascular remodeling. However, the exact relationship between hypertension and vascular remodeling remains to be elucidated.