Angiotensin II type 1A receptor expressed in smooth muscle cells is required for hypertensive vascular remodeling in mice infused with angiotensin II
Authors: Okuno Keisuke , Torimoto Keiichi , Sparks Matthew , Eguchi Satoru 
Published: May 2023

Angiotensin II (AngII) and its AngII type-1 (AT1) receptors play critical roles in cardiovascular diseases such as hypertension. Rodents have two types of AT1 receptor (AT1A and AT1B) of which knock-in Tagln-mediated smooth muscle AT1A receptor silencing attenuated AngII-induced hypertension. Although vascular remodeling, a significant contributor to organ damage, occurs concurrently with hypertension in AngII infused mice, the contribution of smooth muscle AT1A receptor in this process remains unexplored. The objective of this study is to explore the involvement of the smooth muscle AT1A receptor in cardiovascular remodeling utilizing a mouse model of hypertension via AngII infusion. It is hypothesized that smooth muscle AT1A receptors exclusively contribute to both medial thickening and adventitial fibrosis regardless of the presence of hypertension. 1 μg/kg/min AngII was infused for 2 weeks in two distinct AT1A receptor silenced mice, knock-in Tagln-mediated constitutive smooth muscle AT1A receptor silenced mice (in which both smooth muscle and cardiac myocyte AT1A receptor expressions were attenuated) and Myh11-mediated inducible smooth muscle AT1A together with global AT1B silenced mice (in which smooth muscle but not cardiac myocyte AT1A receptor expression was attenuated) for evaluation of hypertension and vascular remodeling. Masson’s trichrome staining, Sirius red staining and immunohistochemistry (collagen-III and CD45) in aortas were performed to assess medial thickening, perivascular fibrosis, and leucocyte infiltration. Heart weight body weight ratio and echocardiogram were used to assess cardiac hypertrophy. Telemetry was used for blood pressure assessments. Medial thickness, adventitial collagen deposition and immune cell infiltration in aorta were increased in control mice but not in both smooth muscle AT1A receptor silenced mice. Coronary arterial perivascular fibrosis in response to AngII infusion was also attenuated in both AT1A receptor silenced mice. AngII-induced cardiac hypertrophy was attenuated in constitutive smooth muscle AT1A receptor silenced mice. However, AngII-induced cardiac hypertrophy and hypertension were not altered in inducible smooth muscle AT1A receptor silenced mice. In conclusion, smooth muscle AT1A receptor stimulation appears to be a primary driver for vascular remodeling associated with medial thickening, adventitial fibrosis, and vascular inflammation in mice. Hypertension, which is likely driven by a mechanism involving kidney, develops independently from large vessel structural remodeling. Cardiac hypertrophy does not require cardiac or vascular AT1A receptors but is likely driven secondary to hypertension. These findings thus provide a new understanding of the relationship among vascular smooth muscle AT1A receptor and the cardiovascular phenotypes in mice with AngII infusion. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.