Perivascular Adipose Tissue (PVAT) as a Central Integrator of Vascular Health

血管周围脂肪组织 (PVAT) 作为血管健康的核心整合者

• 批准号: 10543504
• 负责人: Stephanie W Watts
• 金额: $ 269.46万
• 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/10543504
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Animals; Applications Grants; Arteries; Bioinformatics; Blood Pressure; Blood Vessels; Blood capillaries; Cardiovascular Diseases; Cardiovascular Physiology; Cell physiology; Cells; Collaborations; Communication; Communities; Complement; Development; Disease; Elements; Excess Mortality; Fatty acid glycerol esters; Fibroblasts; Functional disorder; Genes; Goals; Grant; Health; High Fat Diet; Home; Homeostasis; Human; Human body; Hypertension; Immune; Inbred Dahl Rats; Individual; Informatics; Investments; Knowledge; Laboratory Animals; Learning; Literature; Mechanics; Mesenchymal; Microscopic; Microscopy; Modeling; Mus; Nature; Nerve; Neurons; Obesity; Pathologic; Physiological; Physiology; Program Research Project Grants; Publishing; Rattus; Regulation; Research; Research Personnel; Scientist; Stretching; Systems Integration; Testing; Therapeutic; Therapeutic Intervention; Thoracic aorta; Time; Tissues; Tunica Adventitia; Vascular Diseases; Work; blood pressure regulation; cell type; data sharing; experimental study; fighting; genetic approach; immunoregulation; improved; mechanical force; mechanotransduction; model organism; nerve supply; novel; novel strategies; optogenetics; peripheral blood vessel; pressure; progenitor; response; stem cells; stem-like cell; synergism; transcriptome sequencing; translational potential; vasa vasorum

Summary - Overall Vascular health is essential to the normal regulation of cardiovascular function. That dysfunctions of blood pressure regulation, such as hypertension, remain difficult to treat suggests that the scientific community does not fully understand the mechanisms by which normal and pathological changes in blood pressure are achieved, nor how the vasculature can both influence and be impacted by changes in blood pressure. This new Program Project Grant is based on the overall hypothesis that perivascular adipose tissue (PVAT) has bidirectional interactions with the other layers of a blood vessel and is a critical partner with these layers to form an integrated system that maintains vascular health. Our collective preliminary work has led to the hypothesis that PVAT and its primary components – the adipocyte and progenitor cells, the immune cells, and neuronal innervation/neurohumoral control —are central integrators of overall vascular health/function. This grant will enable foundational studies that are critical to understanding how the elements of PVAT work together, and ultimately influence vascular tone. This grant is unique in that it will also interrogate how (patho)physiological challenges (e.g. change in stretch, pressure) placed on a vessel affect PVAT function. Our studies will progress to a model of high fat (HF)-diet induced hypertension, a situation of elevated vascular pressure and PVAT burden. This work will use models that allow for the most rigorous experimentation: mice in nerve- and adipocyte progenitor lineage-tracing; optogenetic and chemogenetic approaches; rats as a model organism for HF-diet induced hypertension; pressure imposition through a novel mid-thoracic aortic coarcted model; novel microscopic and bioinformatic work; and human vasculature + PVAT for translational potential. Our collective, novel approach contrasts directly with the plethora of literature that investigates how the PVAT secretome influences vascular function. We will determine, through projects supported by four cores (administrative, animal, bioinformatic and microscopy), whether: 1) PVAT possesses the ability to mechanotransduce and has significant stiffness that contributes to vascular stiffness; 2) PVAT is innervated or under neurohumoral control with functional consequence; 3) whether the unique microenvironment of PVAT influences immune cell function; and 4) how the fate of adipocyte progenitors is influenced by vascular stretch. Investigators are deeply invested in the planning of, execution of and learning from experiments carried out in projects and cores other than theirs; this work was purposefully developed in this way to be synergistic. This integrated work advances human health by redefining the functional vessel, a redefinition that could have significant impact on not only hypertension but all physiologies and dysfunctions which involve the vasculature.

摘要 - 总体 血管健康对于正常的心血管功能调节至关重要。血液功能障碍 压力调节（例如高血压）仍然难以治疗，这表明科学界确实 不完全了解实现血压正常和病理变化的机制， 脉管系统如何受到血压变化的影响和影响。这个新程序 项目赠款基于总体假设，即血管周围脂肪组织（PVAT）具有双向 与血管的其他层相互作用，是与这些层形成综合层的关键伴侣 维持血管健康的系统。我们的集体初步工作导致了一个假设，即PVAT 及其主要成分 - 脂肪细胞和祖细胞，免疫细胞和神经元 神经/神经肿瘤控制 - 整体血管健康/功能的中心积分器。这笔赠款 将实现基础研究，这些研究对于了解PVAT的要素如何共同工作以及 最终影响血管张力。这笔赠款是独一无二的 挑战（例如，伸展，压力的变化）会影响PVAT功能。我们的研究将进步 到高脂肪（HF） - diet诱导高血压的模型，血管压力升高和PVAT的情况 负担。这项工作将使用允许最严格实验的模型：神经和脂肪细胞中的小鼠 祖先谱系追踪；光遗传学和化学遗传学方法；大鼠是HF-DIET的模型生物 诱发高血压；压力通过新型的胸腔主动脉核模型施加；小说 微观和生物信息学的工作；和人体脉管系统 + PVAT具有翻译潜力。我们的集体 新颖的方法与大量的文学作品直接形成鲜明对比，该文献调查了PVAT的分泌方式 影响血管功能。我们将通过四个核心支持的项目来确定 动物，生物信息学和显微镜），是否：1）PVAT具有机械转换的能力并具有 显着的刚度有助于血管僵硬； 2）PVAT已支配或在神经肿瘤控制下 具有功能后果； 3）PVAT的独特微环境是否影响免疫细胞功能； 4）脂肪细胞祖细胞的命运如何受到血管拉伸的影响。调查人员深处 在项目和核心中进行的实验中进行的计划，执行和学习的调查 除了他们的；这项工作是有目的地开发的，使其具有协同作用。这整合了 工作通过重新定义功能船来促进人类健康，这是一种可能产生重大影响的重新定义 不仅在高血压上，还包括涉及脉管系统的所有生理和功能障碍。