Regulation of arterial phenotype by perivascular adipose tissue in cardiometabolic disease

肥胖和代谢性疾病是心血管疾病的危险因素，其患病率也在不断上升 导致了我们人群中血管病变率的增加。脂肪细胞具有功能特异性 白色脂肪细胞以脂类(白色脂肪组织)的形式储存能量，以及 生热脂肪细胞燃烧卡路里并产生热量(米色和棕色脂肪组织)。在血管内 微环境，血管周围的脂肪组织(PVAT)包围着血管，影响血管 功能。在小鼠，胸主动脉周围的PVAT呈棕色，具有高水平的生热作用。 标记物，并且与血管反应性和血管疾病进展有明显的关联。在人类中，主动脉 PVAT看起来类似于人类皮下白色脂肪组织，单眼脂肪细胞表现为 脂肪储存表型。然而，我们在人的主动脉PVAT中发现了生热标志物，并且 来自健康和疾病血管系统的人PVAT之间的分子差异是建立的。这个 有研究表明，人体内的生热脂肪组织与白色脂肪组织的比例可以提高。 作为一种抗肥胖的治疗策略，增加PVAT的生热被预测具有保护作用 对抗血管疾病。因此，了解脂肪细胞产热的分子决定因素是至关重要的。 在人类身上。在合作工作中，我们最近定义了新的生热脂肪细胞谱系 在小鼠身上进行了功能测试。有趣的是，这些谱系包括一种类似于脂肪细胞的平滑肌细胞。 血统，与PVAT相关，与血管壁直接相邻。我们假设 人PVAT中的平滑肌细胞样脂肪细胞系对生热脂肪细胞的直接贡献 人类的血统，这种血统的功能活动与血管疾病呈负相关 进步。这是一项翻译研究，有以下具体目的：目的1.定义分子同一性 人PVAT中脂肪细胞前体细胞的组成，以及血管病理中细胞PVAT的组成。我们会 进行分子研究以确定脂肪祖细胞亚群和总体细胞组成 在人类PVAT中，并确定与健康和疾病的临床和生理指标的关联。目标 2.确定人功能性热源性脂肪细胞分化的机制 脂肪细胞前体细胞及其对血管平滑肌细胞生理学的影响。差异化能力将是 在成纤维细胞祖细胞群体和SMC样祖细胞群体中进行测试，以及旁分泌信号转导 将使用人类血管SMC对脂肪细胞进行评估。从分子中鉴定的新途径 研究将为确定生热分化的驱动因素的研究提供信息。我们的结果预计将 首次识别与不同血管病理相对应的PVAT的分子特征，以及 与生热脂肪细胞分化相关的关键脂肪祖细胞群体的特征 人类祖细胞。

Obesity and metabolic disease are risk factors for cardiovascular diseases, and their increasing prevalence has led to increased rates of vascular pathology in our population. Adipocytes have functional specificity based on their molecular phenotype; white adipocytes store energy in the form of lipids (white adipose tissue), and thermogenic adipocytes burn calories and generate heat (beige and brown adipose tissue). Within the vascular microenvironment, blood vessels are surrounded by perivascular adipose tissue (PVAT) that impacts vascular function. In the mouse, PVAT surrounding the thoracic aorta are brown-like, with high levels of thermogenic markers, and a clear association with vascular reactivity and vascular disease progression. In humans, aortic PVAT appears similar to human subcutaneous white adipose tissue, with unilocular adipocytes displaying a lipid storage phenotype. However, we identified thermogenic markers within human aortic PVAT, and molecular differences are established between human PVAT from healthy versus diseased vasculature. The ability to increase the proportion of thermogenic versus white adipose tissue in the body has been suggested to be an anti-obesity therapeutic strategy, and increasing thermogenesis of PVAT is predicted to be protective against vascular disease. Thus, it is critical to understand molecular determinants of adipocyte thermogenesis in humans. In collaborative work, we recently defined novel lineages of thermogenic adipocytes that were functionally tested in mice. These lineages, interestingly, included a smooth muscle cell (SMC) like adipocyte lineage, which is relevant to PVAT, which is directly adjacent to the vessel wall. We hypothesize that the smooth muscle cell-like adipocyte lineage in human PVAT contributes directly to the thermogenic adipocyte lineage in humans, and that the functional activity of this lineage inversely correlates to vascular disease progression. This is a translational study with the following specific aims: Aim 1. Define the molecular identity of the adipocyte progenitor cells in human PVAT, and cellular PVAT composition in vascular pathology. We will perform molecular studies to identify sub-populations of adipocyte progenitors and overall cellular composition in human PVAT, and identify associations with clinical and physiological measures of health and disease. Aim 2. Identify the mechanisms driving functional capacity thermogenic adipocyte differentiation in human adipocyte progenitors, and impact on vascular smooth muscle cell physiology. Differentiation capacity will be tested in the fibroblast progenitor population and the SMC-like progenitor population, and paracrine signaling from adipocytes will be evaluated using human vascular SMC. Novel pathways identified from molecular studies will inform studies to determine drivers of thermogenic differentiation. Our results are expected to identify for the first time molecular signatures of PVAT corresponding to different vascular pathologies, and characterize critical adipocyte progenitor populations related to the differentiation of thermogenic adipocytes in human progenitor cells.