Regulation of arterial phenotype by perivascular adipose tissue in cardiometabolic disease

心脏代谢疾病中血管周围脂肪组织对动脉表型的调节

• 批准号: 10443027
• 负责人: Lucy Liaw
• 金额: $ 57.02万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443027
• 关键词: 3-Dimensional; Abdomen; Abdominal Aortic Aneurysm; Activities of Daily Living; Address; Adipocytes; Adipose tissue; Adult; Affect; Aneurysm; Area; Atherosclerosis; Automobile Driving; Biology; Blood Vessels; Brown Fat; Calories; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular Pathology; Cell Lineage; Cell Nucleus; Cell physiology; Cells; Clinical; Collaborations; Collection; Coronary artery; Diet; Disease; Disease Progression; Fibroblasts; Genetic; Goals; Health; Heart; Human; In Vitro; Laboratories; Lipids; Measures; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Molecular; Molecular Profiling; Mus; NOTCH3 gene; Nature; Newborn Infant; Obesity; Operative Surgical Procedures; Paracrine Communication; Pathology; Pathway interactions; Patients; Phenotype; Physiological; Population; Prevalence; Process; Proteomics; Protocols documentation; Regulation; Research; Role; Severities; Signal Transduction; Smooth Muscle Myocytes; Specificity; Stimulus; Sympathetic Nervous System; Temperature; Testing; Therapeutic; Thermogenesis; Thoracic aorta; Time; Tissue Donors; Tissue Sample; Translational Research; Vascular Diseases; Vascular Smooth Muscle; Work; adipocyte differentiation; base; cardiovascular health; cardiovascular risk factor; human RNA sequencing; insight; interest; lipidomics; molecular phenotype; mouse model; novel; patient population; progenitor; response; stem cells; subcutaneous; transcriptomics; translational approach; translational study

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.

肥胖和代谢性疾病是心血管疾病的危险因素， 导致了我们人群中血管病变的发病率增加。脂肪细胞具有功能特异性 白色脂肪细胞以脂质形式储存能量（白色脂肪组织）， 产热脂肪细胞燃烧卡路里并产生热量（米色和棕色脂肪组织）。血管内 在微环境中，血管被血管周围脂肪组织（PVAT）包围， 功能在小鼠中，胸主动脉周围的PVAT呈棕色，具有高水平的产热性。 标记物，并与血管反应性和血管疾病进展明确相关。在人类中，主动脉 PVAT看起来与人皮下白色脂肪组织相似，单室脂肪细胞显示出 脂质储存表型然而，我们在人主动脉PVAT中鉴定了产热标记物， 在来自健康与患病脉管系统的人PVAT之间建立了分子差异。的 已经提出了增加体内产热脂肪组织相对于白色脂肪组织的比例的能力 是一种抗肥胖的治疗策略，增加PVAT的产热被预测是保护性的。 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，我们最近定义了产热脂肪细胞的新谱系， 在小鼠中进行功能测试。有趣的是，这些谱系包括平滑肌细胞（SMC）样脂肪细胞 与PVAT相关的细胞系，其直接邻近血管壁。我们假设 人PVAT中的平滑肌细胞样脂肪细胞谱系直接有助于产热脂肪细胞 该谱系的功能活性与血管疾病呈负相关 进展这是一项翻译研究，具有以下具体目标：目标1。定义分子身份 人PVAT中脂肪细胞祖细胞的组成，以及血管病理学中细胞PVAT的组成。我们将 进行分子研究以鉴定脂肪祖细胞的亚群和总体细胞组成 在人类PVAT中，并鉴定与健康和疾病的临床和生理测量的关联。目的 2.确定驱动人类功能性产热脂肪细胞分化的机制 脂肪祖细胞，以及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了测试， 将使用人血管SMC评价来自脂肪细胞的细胞。从分子水平鉴定的新途径 研究将为确定生热分化驱动因素的研究提供信息。我们的结果预计将 首次鉴定对应于不同血管病变的PVAT分子特征，和 表征与产热脂肪细胞分化相关的关键脂肪细胞祖细胞群， 人类祖细胞