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被狭窄地视为通过分泌物与血管通信的组织 和免疫细胞的归巢。这是“外部”通信，是PVAT的被动函数。我们 假设要维持对组织健康至关重要的体内稳态，必须有一个“内而外” 从正式接受的船只层（Intima，Media，Adventitia）的通信到PVAT 机械性质。这使血管可以将其状态告知PVAT，以便PVAT可以做出回应 适当地维持体内平衡。如果是PVAT进行分泌物，那可能不是 不知情/被动，而是回应从周围血管中收到的消息。项目i 总体假设是PVAT机械地与血管控制血管 音调，有助于（病原）生理功能。 我们建议对以前尚未考虑的两个（2）个PVAT功能进行调查以及哪些 对血管功能产生深远的影响。我们的第一个假设是压力传播到PVAT 通过机械敏感元素（AIM 1）。在体内所有脂肪组织中，PVAT被启发为 机械响应性是因为它会暴露于恒压。其次，我们假设PVAT有一个 自身的动态机械刚度可降低健康中的血管刚度（AIM 2）。此外，变化 这种动态僵硬是随着疾病而发生的（例如僵硬的增加）。我们共享支持的初步数据 这两个假设。在健康组织中的PVAT是血管降低容器音调和刚度不可或缺的一部分。那， 该理解的血管层必须被视为临床上相关的组织。两个目标分别集中 在这些新参数上。我们将整合其他项目的信息，以了解神经和 神经递质（项目II），免疫电池（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机械转导（AIM 1）和刚度（AIM 2）在健康中。核心b 提供高脂肪（HF）饮食诱导的高血压（具有非高血压DAHL R控制的DAHL S）以及 新型的胸腔主动脉齐乳牵引模型可施加升高的压力，而不是饮食。核心有并且将 继续提供RNA测序分析，以确定支持PVAT内的特定细胞类型 机械转导。核心D将在测量非细胞贡献方面具有明显的帮助 胶原蛋白和弹性蛋白。当这些差距填补时，我们的工作将证明应始终考虑PVAT 正式血管的活跃伴侣。我们要重新定义什么是正式的血管 这个新知识。