The contribution of perivascular adipose tissue macrophages to microvascular dysfunction in obesity

血管周围脂肪组织巨噬细胞对肥胖微血管功能障碍的贡献

• 批准号: 10326354
• 负责人: Carl White
• 金额: $ 39万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-19 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326354
• 关键词: Adipocytes; Adipose tissue; Affect; Animals; Anti-Inflammatory Agents; Back; Biological Assay; Biological Availability; Blood Vessels; Cells; Clinical; Communication; Data; Development; Diet; Event; Fatty acid glycerol esters; Female; Fibroblasts; Functional disorder; Genes; Goals; Health; Hydrogen Sulfide; Hypertension; Immune; Immune response; Immune system; Impairment; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Knock-out; Knowledge; Light; Measures; Mediating; Mesentery; Metabolic; Microvascular Dysfunction; Mission; Modeling; Monitor; Mus; Myography; NADPH Oxidase; NOS2A gene; Nature; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organism; Oxidation-Reduction; Paracrine Communication; Peroxonitrite; Physiological; Physiology; Play; Positioning Attribute; Prevention; Reactive Nitrogen Species; Research; Role; Signal Transduction; Signaling Molecule; Testing; Thinness; Tissues; United States National Institutes of Health; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; confocal imaging; defined contribution; disease phenotype; human disease; in vivo; intravital microscopy; macrophage; male; mouse model; obesity development; pressure; recruit; vascular bed

PROJECT SUMMARY Obesity causes microvascular dysfunction. The mechanisms that underpin the initiation and progression of microvascular dysfunction are not known. This fundamental gap is a problem because microvascular dysfunction precedes, and likely contributes to, the development of insulin resistance, hypertension, and type-2 diabetes. The perivascular adipose tissue (PVAT) that surrounds vessels plays a physiological role in regulating vascular function. Preliminary data from the applicant’s lab show that proinflammatory macrophages within the PVAT mediate microvascular dysfunction in obesity, and that macrophages release redox species that impinge on microvascular function by modulating crosstalk between vessel nitric oxide and the gaseous signaling molecule hydrogen sulfide. The objective of the current proposal is to define the role of PVAT macrophages in the initiation and progression of microvascular dysfunction during obesity. The objective will be accomplished by testing the central hypothesis that proinflammatory macrophages drive microvascular disease during obesity by infiltrating the PVAT and releasing reactive nitrogen species, which limits nitric oxide bioavailability and increase contractility by depleting vessel hydrogen sulfide. Three specific aims are proposed: aim 1 will define the contribution of PVAT inflammation to the initiation and progression of microvascular disease; aim 2 identify the paracrine signal that mediates communication between PVAT- macrophages and the microvasculature, and aim 3 will define mechanisms by which PVAT-macrophages affect microvascular signal transduction. A diet-induced mouse model of obesity will be used in combination with macrophage depletion and tissue-specific knockouts. A comprehensive in vivo and in vitro analysis of the interaction between PVAT, macrophages, and microvasculature will be performed in both male and female animals by integrating data from intravital microscopy, pressure myography, confocal imaging of live mesenteric arteriolar segments, and metabolic analyses. Completion of these aims will establish a new paradigm in which recruitment of proinflammatory macrophages to the PVAT is a major catalyzing event in the development and progression of microvascular dysfunction.

项目摘要 肥胖导致微血管功能障碍。的启动和进展的机制， 微血管功能障碍是未知的。这个基本的差距是一个问题，因为微血管 胰岛素抵抗、高血压和2型糖尿病是胰岛素抵抗、高血压和2型糖尿病的先兆， 糖尿病围绕血管的血管周围脂肪组织（PVAT）在以下方面发挥生理作用： 调节血管功能。申请人实验室的初步数据显示，促炎性巨噬细胞 PVAT内介导肥胖症微血管功能障碍，巨噬细胞释放氧化还原物质 通过调节血管一氧化氮和气体之间的串扰来影响微血管功能， 信号分子硫化氢。本提案的目的是界定PVAT的作用 巨噬细胞在肥胖期间微血管功能障碍的启动和进展中的作用。这一目标的方式是 通过测试促炎巨噬细胞驱动微血管的中心假设来实现 肥胖期间的疾病通过浸润PVAT和释放活性氮物质，限制一氧化氮 生物利用度和通过消耗血管硫化氢增加收缩性。三个具体目标是 提出：目的1将定义PVAT炎症对PVAT启动和进展的贡献， 微血管疾病;目的2确定介导PVAT- 目的3将定义PVAT-巨噬细胞和微血管系统的机制， 影响微血管信号转导。饮食诱导的肥胖小鼠模型将与 巨噬细胞耗竭和组织特异性基因敲除一个全面的体内和体外分析， 将在雄性和雌性动物中进行PVAT、巨噬细胞和微血管系统之间的相互作用 通过整合来自活体显微镜、压力肌造影、活体共聚焦成像的数据， 肠系膜小动脉段和代谢分析。这些目标的实现将建立一个新的 其中促炎性巨噬细胞向PVAT的募集是PVAT中的主要催化事件的范例。 微血管功能障碍的发展和进展。