PVAT mechanics in health and disease

PVAT 力学在健康和疾病中的应用

• 批准号: 10331578
• 负责人: Stephanie W Watts
• 金额: $ 33.4万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-22 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331578
• 关键词: Adipocytes; Adipose tissue; Angiotensin II; Aortic coarctation; Arteries; Blood; Blood Vessels; Blood flow; Cells; Chemicals; Chest; Collagen; Communication; Communications Media; Contracts; Data; Diet; Disease; Disease Progression; Elastin; Elements; Environment; Excision; Exposure to; Goals; Health; Heart; High Fat Diet; Homeostasis; Homing; Hypertension; Immune; Impairment; Individual; Investigation; Knowledge; Maintenance; Measures; Mechanics; Modeling; Nature; Neurotransmitters; Nutrient; Physiological; Property; Relaxation; Signal Transduction; Solid; Stress; Stretching; Testing; Thoracic aorta; Tissues; Tunica Adventitia; Whole Blood; Work; adiponectin; blood pressure elevation; cell type; clinically relevant; experimental study; improved; intima media; mechanotransduction; nerve supply; novel; peripheral blood vessel; pressure; response; transcriptome sequencing; wasting

Project Summary – Project I PVAT has been narrowly viewed as a tissue that communicates with the blood vessel through secretions and homing of immune cells. This is `outside-in' communication and is a passive function of PVAT. We hypothesize that to maintain the homeostasis so critical to tissue health, there must be an `inside-out' communication from the formally accepted vessel layers – intima, media, adventitia – to the PVAT that is mechanical in nature. This allows the blood vessel to inform PVAT of its status, such that PVAT can respond appropriately to maintain homeostasis. Thus, if secretions are made by PVAT, this may not be uninformed/passive, but rather in response to messages received from the blood vessel it surrounds. Project I overall hypothesis is that PVAT mechanically coordinates with the blood vessel in control of vascular tone, contributing to (patho)physiological function. We propose investigation of two (2) functions of PVAT that have not been previously considered and which exert profound effects on vascular function. Our first hypothesis is that pressure is transmitted to PVAT through mechanosensitive elements (Aim 1). Of all the adipose tissues in the body, PVAT is primed to be mechanoresponsive because it is exposed to constant pressure. Second, we hypothesize that PVAT has a dynamic mechanical stiffness of its own that reduces vascular stiffness in health (Aim 2). Further, changes in this dynamic stiffness occur with disease (e.g. increased stiffening). We share preliminary data that support both hypotheses. PVAT, in healthy tissue, is integral to the vessel reduced vessel tone and stiffness. Thus, this understudied vessel layer must be considered as a clinically relevant tissue. Two aims focus individually on these new parameters. We will integrate information from other projects in how innervation and neurotransmitters (Project II), immune cells (Project III), and direct influence of stretch on adipocyte/SVF function (Project IV) impact PVAT mechanotransduction (Aim 1) and stiffness (Aim 2) in health. Core B provides high fat (HF) diet-induced hypertension (Dahl S with non-hypertensive Dahl R control) as well as a novel mid-thoracic aorta coarcted model to impose elevated pressure independent of diet. Core C has and will continue to provide RNA sequencing analysis for determination of specific cell types within PVAT that support mechanotransduction. Core D will be of marked assistance in measuring non cellular contributions made by collagens and elastin. When these gaps are filled, our work will justify that PVAT should always be considered an active partner of the formal blood vessel. We stand to redefine what is the formal blood vessel with this new knowledge.

项目概要-项目I PVAT一直被狭义地视为通过分泌物与血管沟通的组织 和免疫细胞的归巢。这是“由外而内”的交流，是PVAT的一种被动功能。我们 假设为了维持对组织健康如此重要的内稳态，必须有一个“由内而外”的过程， 从正式接受的血管层-内膜、中膜、外膜-到PVAT的通信， 机械性质。这允许血管通知PVAT其状态，使得PVAT可以响应 以维持体内平衡。因此，如果分泌物是由PVAT产生的，则这可能不是 这是不知情的/被动的，而是响应于从其周围的血管接收的消息。项目我 总的假设是PVAT与血管机械协调以控制血管收缩。 音调，有助于（病理）生理功能。 我们建议研究PVAT的两（2）个功能，这些功能以前没有考虑过， 对血管功能产生深远的影响。我们的第一个假设是压力传递到PVAT 通过机械敏感元件（目标1）。在体内所有的脂肪组织中，PVAT被认为是 因为它暴露在恒定的压力下。其次，我们假设PVAT具有 其自身的动态机械刚度降低健康时的血管刚度（目标2）。此外， 这种动态刚度随着疾病（例如，增加的硬化）而发生。我们分享了初步数据， 两种假设。在健康组织中，PVAT是血管的组成部分，降低了血管张力和硬度。因此，在本发明中， 该未充分研究的血管层必须被认为是临床相关组织。两个目标各自聚焦 这些新参数。我们将整合来自其他项目的信息，了解神经支配和 神经递质（项目II），免疫细胞（项目III），以及拉伸对脂肪细胞/SVF的直接影响 功能（项目IV）影响PVAT机械传导（目标1）和硬度（目标2）。核心B 提供高脂肪（HF）饮食诱导的高血压（Dahl S与非高血压Dahl R对照）以及 新的胸中主动脉缩窄模型，以独立于饮食施加升高的压力。核心C已经并将 继续提供RNA测序分析，以确定PVAT中的特定细胞类型， 机械传导核心D将在测量非细胞贡献方面具有显著的帮助， 胶原蛋白和弹性蛋白。当这些空白被填补时，我们的工作将证明PVAT应始终被考虑 正式血管的活跃伙伴。我们站在重新定义什么是正式的血管， 这些新知识。