Essential role of perivascular adipose tissue in blood pressure regulation

血管周围脂肪组织在血压调节中的重要作用

• 批准号: 8670864
• 负责人: Lin Chang
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670864
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Affect; Angiotensin II; Angiotensinogen; Animal Model; Antihypertensive Agents; Aorta; Atherosclerosis; Binding; Biological Assay; Biology; Blood Pressure; Blood Vessels; Boxing; Cardiac; Cardiovascular Diseases; Cells; Chest; Circadian Rhythms; Clinical Research; Crossbreeding; Data; Development; Dimensions; Drops; Exhibits; Fatty acid glycerol esters; Figs - dietary; Framingham Heart Study; Functional disorder; Genetic Transcription; Goals; Homeostasis; Hormones; Human; Hypertension; Hypotension; In Vitro; Knock-out; Knockout Mice; Lead; Literature; Losartan; Maintenance; Messenger RNA; Modeling; Mus; Muscle; PPAR gamma; Pattern; Peripheral; Peroxisome Proliferator-Activated Receptors; Phase; Physiological; Physiology; Plasma; Publishing; Rattus; Regulation; Renin; Renin-Angiotensin System; Reporting; Resting Phase; Role; Saphenous Vein; Smooth Muscle Myocytes; Stroke; Testing; Tissue Donors; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Vascular Diseases; Vascular Endothelial Cell; Visceral; Work; adipokines; autocrine; base; blood pressure regulation; constriction; in vivo; internal thoracic artery; loss of function; mouse model; novel diagnostics; novel therapeutic intervention; overexpression; prevent; promoter; public health relevance; receptor; suprachiasmatic nucleus; uncoupling protein 1; vasoconstriction

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.

描述(申请人提供)：包围大多数血管的血管周围脂肪组织(PVAT)产生不确定的或特征较少的因子，可靶向内皮细胞和血管平滑肌细胞，因此有助于维持血管内环境的稳定。此外，PVAT实际上是一个独特的功能血管层，积极促进血管功能和功能障碍。Framingham心脏研究支持PVAT容量与较高的胸主动脉和腹主动脉内径相关，表明PVAT有助于主动脉重塑。在静息状态下，PVAT的丢失会导致低血压，从而导致勺型血压，但PVAT与血压调节之间的生理关系及其可能的潜在机制仍有待解决。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，大量的初步数据显示，血管紧张素原在PVAT中的表达具有昼夜节律，活动期表达较高，静止期表达较低。该项目将检验核心假设，即PVAT对维持静息时的血压至关重要，PVAT中的局部血管紧张素原是调节静息时血压的主要分子之一，利用新开发的缺乏PVAT的独特动物模型，体内和体外获得和丧失功能的方法，以及用生理学相关的实验方法评估血压和PVAT的生理和功能。这项建议的目的是：1)。明确静息状态下PVAT在血压调节中的重要作用；确定缺乏PVAT的小鼠的低血压是否由血管紧张素原缺乏所致；以及3)。探讨血管紧张素原在PVAT中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生物学和高血压在心血管疾病中的作用产生深远的影响。