Bmal1 in Perivascular Adipose Tissue Regulates Resting Phase Blood Pressure Through Transcriptional Regulation of Angiotensinogen
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 regarding 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 (Agt) knock out mice we determined the vasoactivity of homogenized PVAT in aortic rings and how brown-adipocyte peripheral expression of Bmal1 and Agt in PVAT regulate 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 super-dipper 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 mice (BA-Bmal1-KO). The PVAT contractile properties are mediated by local angiotensin II (Ang II), operating through angiotensin II type 1 receptor-dependent signaling in the isolated vessels and is linked to PVAT circadian regulation of Agt. Indeed, Agt mRNA and Ang II levels in PVAT of BA-Bmal1-KO mice were significantly reduced. Systemic infusion of Ang II, in turn, reduced Bmal1 expression in PVAT while eliminating the hypotensive phenotype during the resting phase in BA-Bmal1-KOmice. Agt, highly expressed in PVAT, shows circadian expression in PVAT and selective deletion of Agt in brown adipocytes recapitulates the phenotype of selective deletion of Bmal1 in brown adipocytes. Furthermore, Agt is a transcriptional target of Bmal1 in PVAT.
Conclusions—These data indicate that local Bmal1 in PVAT regulates Agt expression and the ensuing increase in Ang II, which acts on smooth muscle cells (SMCs) in the vessel walls to regulate vasoactivity and blood pressure on a circadian fashion during the resting phase. These findings will contribute to better understand cardiovascular complications of circadian disorders, alterations in the circadian dipping phenotype and the crosstalk between systemic and peripheral regulation of blood pressure.
- Received June 13, 2017.
- Revision received January 9, 2018.
- Accepted January 16, 2018.