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.

总结 - 总体 血管健康对于心血管功能的正常调节至关重要。 压力调节，例如高血压，仍然难以治疗，这表明科学界确实 不完全了解血压正常和病理变化的机制， 也没有脉管系统如何影响血压的变化以及受血压变化的影响。 项目资助基于血管周围脂肪组织（PVAT）具有双向性的总体假设 与血管的其他层相互作用，并且是与这些层形成集成的关键合作伙伴 我们集体的初步工作得出了 PVAT 的假设。 及其主要成分——脂肪细胞和祖细胞、免疫细胞和神经元 神经支配/神经体液控制——是整体血管健康/功能的核心整合者。 将开展对于理解 PVAT 各要素如何协同工作至关重要的基础研究，以及 最终影响血管张力。这项资助的独特之处在于它还将探讨（病理）生理学的方式。 血管上的挑战（例如拉伸、压力的变化）会影响 PVAT 功能，我们的研究将会取得进展。 高脂肪 (HF) 饮食诱发的高血压模型，血管压力和 PVAT 升高 这项工作将使用允许进行最严格实验的模型：神经细胞和脂肪细胞中的小鼠。 祖细胞谱系追踪；光遗传学和化学遗传学方法；大鼠作为 HF 饮食的模型生物； 通过新型中胸主动脉缩窄模型诱导高血压； 微观和生物信息工作；以及人类脉管系统 + PVAT 的转化潜力。 新颖的方法与大量研究 PVAT 分泌蛋白组的文献形成鲜明对比 我们将通过四个核心支持的项目（行政、 1）PVAT具有力传导能力，并具有 导致血管僵硬的显着僵硬；2) PVAT 受神经支配或受神经体液控制 具有功能性后果；3）PVAT独特的微环境是否影响免疫细胞功能； 4）血管拉伸如何影响脂肪细胞祖细胞的命运。 投资于项目和核心实验的规划、执行和学习 与他们不同的是，这项工作是有目的地以这种方式开发的，以实现协同作用。 通过重新定义功能性血管来促进人类健康，这种重新定义可能会产生重大影响 不仅涉及高血压，还涉及涉及脉管系统的所有生理和功能障碍。