Bmal1 in Perivascular Adipose Tissue Regulates Resting-Phase Blood Pressure Through Transcriptional Regulation of Angiotensinogen

作者：Lin Chang, Wenhao Xiong, Xiangjie Zhao, Yanbo Fan, Yanhong Guo, Minerva T. Garcia-Barrio, Jifeng Zhang, Zhisheng Jiang, Jiandie D. Lin, Yujie Chen · 发表于：Circulation · 年份：2018 · DOI：10.1161/circulationaha.117.029972 · 被引用次数：110 · 研究领域：Cardiovascular Disease and Adiposity、Adipose Tissue and Metabolism、Eicosanoids and Hypertension Pharmacology

BACKGROUND: The perivascular adipose tissue (PVAT) surrounding vessels constitutes a distinct functional integral layer of the vasculature required to preserve vascular tone under physiological conditions. However, there is little information on the relationship between PVAT and blood pressure regulation, including its potential contributions to circadian blood pressure variation. METHODS: Using unique brown adipocyte-specific aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and angiotensinogen knockout mice, we determined the vasoactivity of homogenized PVAT in aortic rings and how brown adipocyte peripheral expression of Bmal1 and angiotensinogen in PVAT regulates the amplitude of diurnal change in blood pressure in mice. RESULTS: We uncovered a peripheral clock in PVAT and demonstrated that loss of Bmal1 in PVAT reduces blood pressure in mice during the resting phase, leading to a superdipper phenotype. PVAT extracts from wild-type mice significantly induced contractility of isolated aortic rings in vitro in an endothelium-independent manner. This property was impaired in PVAT from brown adipocyte-selective Bmal1-deficient (BA-Bmal1-KO) mice. The PVAT contractile properties were mediated by local angiotensin II, operating through angiotensin II type 1 receptor-dependent signaling in the isolated vessels and linked to PVAT circadian regulation of angiotensinogen. Indeed, angiotensinogen mRNA and angiotensin II levels in PVAT of BA-Bmal1-KO mice were sig...