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

总结-总体 血管健康对心血管功能的正常调节至关重要。血液功能障碍 压力调节，如高血压，仍然很难治疗，这表明科学界确实 不完全理解血压正常和病理变化的机制， 也不知道脉管系统如何能够影响血压的变化以及如何被血压的变化影响。这个新项目 资助项目基于血管周围脂肪组织（PVAT）具有双向性的总体假设。 它与血管的其他层相互作用，是这些层形成整合的关键伙伴。 维持血管健康的系统。我们的集体初步工作导致了PVAT的假设， 及其主要成分-脂肪细胞和祖细胞，免疫细胞和神经细胞 神经支配/神经体液控制-是整体血管健康/功能的中心整合者。这笔赠款 将实现对理解PVAT要素如何协同工作至关重要的基础研究， 最终影响血管张力。这项补助金是独一无二的，因为它也将询问如何（病理）生理 施加在血管上的挑战（例如拉伸、压力变化）影响PVAT功能。我们的学习会进步的 高脂饮食诱导的高血压模型，血管压力和PVAT升高的情况 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;大鼠作为HF饮食的模式生物 诱导性高血压;通过新型胸中主动脉缩窄模型施加压力;新型 显微镜和生物信息学工作;以及人类脉管系统+ PVAT用于翻译潜力。我们的集体， 一种新的方法与大量的文献直接形成对比，这些文献研究了PVAT分泌蛋白是如何 影响血管功能。我们将通过四个核心（行政， 动物，生物信息学和显微镜），是否：1）PVAT具有机械性的能力，并具有 导致血管僵硬的显著僵硬; 2）PVAT受神经支配或受神经体液控制 PVAT的独特微环境是否影响免疫细胞功能; 以及4）血管拉伸如何影响脂肪祖细胞的命运。调查人员深感 投资于项目和核心实验的规划、执行和学习 除了他们之外;这项工作是有目的地以这种方式发展的，以便发挥协同作用。这一综合 工作通过重新定义功能性血管来促进人类健康，重新定义可能会产生重大影响 不仅对高血压，而且对涉及脉管系统的所有生理和功能障碍。

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.