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

摘要--总体 血管健康对心血管功能的正常调节至关重要。血液机能失调 血压调节，如高血压，仍然难以治疗，这表明科学界确实如此。 不完全了解血压正常和病理变化的机制， 也不知道血管系统如何影响血压的变化以及如何被血压变化影响。这一新计划 Grant项目基于这样的总体假设：血管周围脂肪组织(PVAT)具有双向 与血管的其他层相互作用，是这些层的关键合作伙伴，形成完整的 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、免疫细胞和神经元 神经支配/神经体液控制-是整体血管健康/功能的中心整合因素。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性研究，以及 最终影响血管张力。这项授权是独一无二的，因为它还将询问如何(PATO)生理 施加在血管上的挑战(如拉伸、压力的变化)会影响PVAT的功能。我们的学习会有进步的 高脂(HF)饮食诱导的高血压模型，血管压力升高和PVAT 负担。这项工作将使用允许进行最严格实验的模型：小鼠的神经和脂肪细胞 祖代血统追踪；光遗传和化学遗传方法；大鼠作为HF饮食的模式生物 诱发性高血压；通过新的胸主动脉缩窄模型施加压力； 显微和生物信息学工作；以及人类血管系统+PVAT的翻译潜力。我们这个集体， 新的方法与过多的研究PVAT如何分泌的文献形成了直接对比 影响血管功能。我们将通过四个核心支持的项目(行政、 动物、生物信息学和显微镜)，是否：1)PVAT具有机械传递能力和 显著的僵硬导致血管僵硬；2)PVAT神经支配或受神经体液控制 3)PVAT独特的微环境是否影响免疫细胞功能； 4)血管拉伸对脂肪细胞前体细胞命运的影响。调查人员对此深感不安 投资于项目和核心中进行的实验的规划、执行和学习 与他们的不同；这项工作是故意以这种方式发展起来的，以实现协同增效。这一集成 这项工作通过重新定义功能性血管来促进人类健康，这一重新定义可能会产生重大影响 不仅是高血压，还有涉及血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.