Essential role of perivascular adipose tissue in blood pressure regulation

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DESCRIPTION (provided by applicant): Perivascular adipose tissue (PVAT), which surrounds most vessels, produces undetermined or less characterized factors that could target endothelial cells and vascular smooth muscle cells, and herein contribute to the maintenance of vessel homeostasis. Also, PVAT is de facto a distinct functional vascular layer actively contributing to vascular function and dysfunction. The Framingham Heart Study supports that PVAT volume is associated with higher thoracic and abdominal aortic dimensions, suggesting that PVAT contributes to aortic remodeling. Loss of PVAT in mice are hypotensive during resting phase, which leads to dipper blood pressure, but a physiological relationship between PVAT and regulation of blood pressure and the possible underlying mechanisms remains to be addressed. Angiotensinogen, one of components of renin angiotensin system, is produced in adipocytes and regulates blood pressure through autocrine manner. However, extensive preliminary data here show angiotensinogen expression in PVAT in a circadian rhythm manner, which is higher in active phase and lower in resting phase. The proposed project will test the central hypothesis that PVAT is critical to maintain blood pressure in resting phase, and local angiotensinogen in PVAT is one of predominant molecules that regulates blood pressure in resting phase taking advantage of newly developed unique animal models lacking PVAT, gain- and loss-of-function approaches in vivo and in vitro, and assessment of blood pressure and PVAT physiology and function with physiologically relevant experimental approaches. The aims of this proposal are: 1). Define a critical role of PVAT on blood pressure regulation in resting phase; 2). Determine whether hypotension in mice lacking PVAT is due to angiotensinogen deficiency; and 3). Determine the mechanisms of circadian rhythm regulation of angiotensinogen in PVAT and the effects on blood vessel tone. The results of this proposal will have profound implications on the understanding of PVAT biology and hypertension in cardiovascular diseases.