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 被狭隘地视为通过分泌物与血管沟通的组织 这是“由外向内”的通讯，是 PVAT 的被动功能。 坚持认为，为了维持对组织健康至关重要的稳态，必须有一个“由内而外”的机制 从正式接受的血管层（内膜、中膜、外膜）到 PVAT 的通信 本质上是机械的，这使得血管可以告知 PVAT 其状态，以便 PVAT 可以做出反应。 因此，如果分泌物是由 PVAT 产生的，则可能不会。 不知情/被动，而是响应从项目 I 周围的血管收到的信息。 总体假设是PVAT与血管机械协调控制血管 音调，有助于（病理）生理功能。 我们研究了先前未考虑过的 PVAT 两 (2) 项功能的提案，其中 我们的第一个假设是压力传递至 PVAT。 通过机械敏感元件（目标 1），PVAT 已准备好成为体内所有脂肪组织中的一员。 其次，我们认为 PVAT 具有机械响应性。 其自身的动态机械刚度可降低健康中的血管刚度（目标 2）。 这种动态僵硬随着疾病而发生（例如僵硬增加），我们分享支持的初步数据。 这两种假设都表明，在健康组织中，PVAT 是血管不可或缺的一部分，可降低血管张力和硬度。 必须将这一待研究的血管层视为临床相关组织，分别关注两个目标。 关于这些新参数，我们将整合其他项目的信息，了解如何进行神经支配和控制。 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）影响健康中的 PVAT 机械转导（目标 1）和硬度（目标 2）。 提供高脂肪 (HF) 饮食诱发的高血压（Dahl S 与非高血压 Dahl R 对照）以及 新型中胸主动脉缩窄模型可以独立于饮食而施加升高的压力。 继续提供 RNA 测序分析，以确定 PVAT 内的特定细胞类型，支持 核心 D 将在测量非细胞贡献方面提供显着帮助。 当这些空白被填补时，我们的工作将证明PVAT应该始终被考虑。 正式血管的积极合作伙伴，我们将重新定义什么是正式血管。 这个新知识。