Smooth Muscle At1a Receptor Mediates Perivascular Fibrosis in Angiotensin II‐infused Mice

Abstract

Angiotensin II (Ang II) signaling via AT1 receptor has been shown to play a critical role in the pathogenesis of hypertension, cardiovascular hypertrophy and fibrosis. We have demonstrated that ADAM17 expressed in vascular smooth muscle cells (VSMC) mediates EGF receptor activation and promotes cardiac hypertrophy and perivascular fibrosis induced by Ang II. It is conceivable that Ang II signaling in VSMCs specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis. In a recent study, deficiency of smooth muscle AT1a receptors results in diminished hypertension and protection from cardiac hypertrophy induced by Ang II. However, we have limited understanding whether smooth muscle AT1a receptors affects hypertensive fibrosis in vasculature. Thus, this study was designed to elucidate the roles of the AT1a receptor in VSMCs in cardiovascular remodeling including fibrosis during Ang II stimulation using VSMC AT1a receptor deficient mice. To delete the AT1a receptor from VSMCs, we crossed C57BL/6 transgenic mouse lines expressing Cre recombinase under the control of the endogenous sm22α promoter (Kock‐In, KIsm22α‐Cre). Male AT1a flox/flox KIsm22α‐Cre+/‐ (SMKO) and control (AT1a flox/flox KIsm22α‐Cre‐/‐) mice were infused with Ang II (1 µg/kg/min) for 2 weeks via osmotic mini‐pump. In control mice, Ang II infusion for 2 weeks induced cardiac hypertrophy indicated by heart‐to‐body weight ratio and echocardiogram. After 2 weeks of Ang II infusion, heart‐to‐body weight ratios were significantly increased in control mice compared with AT1a SMKO mice (6.04 versus 4.89, respectively, p=0.032). Cardiac wall hypertrophy was seen in control mice after 2 weeks of Ang II infusion, which was attenuated in AT1a SMKO mice. Control mice (n=5) showed vascular medial hypertrophy and perivascular fibrosis in coronary arteries, whereas these phenotypic changes were attenuated in SMKO mice (96.8 µm vs. 56.4 µm, respectively, p<0.0001). In conclusion, AT1a receptors expressed in VSMC could mediate Ang II‐induced cardiovascular hypertrophy and perivascular fibrosis. Whether the data can be fully explained by the prevention of hypertension remains to be determined. Our data also contrast with the past manuscript showing a protective effect in AT1a flox/flox S100A4‐Cre+/‐ (fibroblast silencing) but not in AT1a flox/flox sm22α‐Cre+/‐ mice with Ang II infusion.