Abstract P112: Bmal1 in Perivascular Adipose Tissues Regulates Blood Pressure Rhythmicity via Angiotensinogen

Abstract

Background: the perivascular adipose tissue (PVAT), surrounding vessel walls, constitutes a distinct functional integral layer of the vascular wall. Presence of a functional PVAT is beneficial for the regulation of vascular tone under physiological conditions while dysfunctional PVAT may promote damage of the vessel wall and development of cardiovascular diseases. However, there is little mechanistic information regarding the relationship between PVAT and blood pressure regulation. Methods: We investigated the vasoactivity of mouse vessel rings in response to homogenized PVAT and how Bmal1 and angiotensinogen in PVAT regulate the rhythmicity of blood pressure in mice. Results: Our results demonstrate that loss of Bmal1 in PVAT reduces blood pressure of mice during the rest phase. PVAT extracts significantly induce contractility of isolated blood vessel rings in vit ro in an endothelium independent manner, and the PVAT extracts from brown adipocyte selective Bmal1 deficient mice result in reduced vessel contractility. The capability of PVAT to stimulate vessel constriction is mediated by angiotensin II (Ang II) signaling present in PVAT evidenced by angiotensinogen being highly expressed in PVAT and the blockage of angiotensin II type 1 receptors in the isolated vessels significantly repressing the pro-contractile effect of PVAT extracts. Consistently, the angiotensinogen mRNA and Ang II levels in PVAT of Bmal1 deficient mice are significantly reduced. Deletion of angiotensinogen in PVAT results in reduced blood pressure in the rest phase as well, and vessel contractility of the PVAT extracts from angiotensinogen deficient mice is significantly reduced. Furthermore, Ang II infusion reduces Bmal1 expression in PVAT. Deletion of angiotensinogen in PVAT decreases expression and phosphorylation of casein kinase -2 alpha and -2 beta (CK2α and CD2β), in turn, enhancing Bmal1 phosphorylation. Conclusions: these data indicate that local Bmal1 in PVAT regulates angiotensinogen expression and secrets Ang II that acts on smooth muscle cells (SMCs) in the vessel walls to regulate vasoactivity and blood pressure.