PVAT mechanics in health and disease

PVAT 力学在健康和疾病中的应用

• 批准号: 10543517
• 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/10543517
• 关键词: Adipocytes; Adipose tissue; Angiotensin II; Aortic coarctation; Arteries; Blood; Blood Vessels; Blood flow; Cells; Chemicals; 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; mechanotransduction; nerve supply; novel; peripheral blood vessel; pressure; response; transcriptome sequencing; transmission process; 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.

项目摘要--项目I PVAT一直被狭隘地视为一种通过分泌物与血管沟通的组织 以及免疫细胞的归巢。这是“由外而内”的沟通，是PVAT的被动功能。我们 假设为了维持对组织健康至关重要的动态平衡，必须有一个由内而外的 从正式接受的血管层--内膜、中膜、外膜--到PVAT即 机械的本质上是机械的这允许血管通知PVAT其状态，以便PVAT可以响应 适当地维持动态平衡。因此，如果分泌物是由PVAT产生的，这可能不是 不知情/被动，而是响应从其周围的血管接收到的消息。项目一 总体假设是PVAT机械地与血管协调控制血管 音调，有助于(悲歌)生理功能。 我们建议研究PVAT的两(2)个函数，这两个函数以前没有被考虑过 对血管功能有深远的影响。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)。在体内的所有脂肪组织中，PVAT被认为是 机械反应，因为它暴露在恒定的压力下。其次，我们假设PVAT有一个 其自身的动态机械刚性可降低健康状态下的血管刚性(目标2)。此外，中国的变化 这种动态僵硬会在疾病时发生(例如，僵化增加)。我们分享的初步数据支持 这两个假设。在健康组织中，PVAT是血管张力和硬度降低的不可或缺的因素。因此， 这一未被研究的血管层必须被视为临床相关组织。两个目标各有侧重 在这些新参数上。我们将整合来自其他项目的信息，了解如何神经支配和 神经递质(项目II)、免疫细胞(项目III)和拉伸对脂肪细胞/SVF的直接影响 功能(项目IV)影响PVAT机械转导(目标1)和僵硬(目标2)的健康。核心B 提供高脂(HF)饮食引起的高血压(达尔·S与非高血压达尔·R对照)以及 新的胸中动脉缩窄模型，施加不依赖饮食的升压。核心C已经并将 继续提供RNA测序分析，以确定PVAT内支持的特定细胞类型 机械转导。核心D将在衡量以下方面的非细胞贡献方面提供显著帮助 胶原蛋白和弹性蛋白。当这些空白被填补时，我们的工作将证明应该始终考虑PVAT 正式血管的活跃伙伴。我们准备重新定义什么是正式的血管 这一新知识。