Essential role of perivascular adipose tissue in blood pressure regulation

描述（由申请人提供）：血管周围脂肪组织（PVAT）包围着大多数血管，产生不确定或特征较少的因子，可靶向内皮细胞和血管平滑肌细胞，并有助于维持血管稳态。此外，PVAT实际上是一个独特的功能血管层，积极参与血管功能和功能障碍。Framingham心脏研究支持PVAT体积与胸腹主动脉尺寸增大有关，提示PVAT有助于主动脉重塑。小鼠在静息期失去PVAT会导致低血压，但PVAT与血压调节之间的生理关系及其可能的机制仍有待研究。血管紧张素原是肾素血管紧张素系统的组成部分之一，由脂肪细胞产生，通过自分泌方式调节血压。然而，广泛的初步数据显示血管紧张素原在PVAT中的表达具有昼夜节律性，在活动期较高，在静息期较低。该项目将利用新开发的独特的缺乏PVAT的动物模型，体内和体外的功能获得和功能丧失方法，以及生理学相关的实验方法来评估血压和PVAT生理和功能，验证PVAT对维持静息期血压至关重要，PVAT中的局部血管紧张素原是静息期调节血压的主要分子之一的中心假设。本建议的目的是：1)。明确PVAT在静息期血压调节中的关键作用；2）. 确定PVAT缺乏小鼠的低血压是否由血管紧张素原缺乏引起；和3)。确定PVAT中血管紧张素原的昼夜节律调节机制及其对血管张力的影响。这一建议的结果将对理解PVAT生物学和心血管疾病中的高血压具有深远的意义。

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.