Perivascular adipose tissue and vascular remodeling

血管周围脂肪组织和血管重塑

• 批准号: 8394712
• 负责人: Neal L Weintraub
• 金额: $ 45.98万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-13 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394712
• 关键词: Address; Adipocytes; Adipose tissue; Angiotensin II; Angiotensin Type 1a Receptor; Angiotensinogen; Arteries; Atherosclerosis; Attenuated; Blood Vessels; Bone Marrow; CCL2 gene; CXCR4 gene; Cardiovascular Diseases; Carotid Arteries; Cells; Communication; Consensus; Coronary; Data; Diet; Fatty acid glycerol esters; Fibroblasts; In Vitro; Infiltration; Inflammation; Inflammatory; Infusion procedures; Injury; Knockout Mice; Laboratories; Mediating; Metabolic; Modeling; Molecular; Mus; Obesity; Obstruction; Pathology; Play; Process; Renin-Angiotensin System; Reporting; Risk Assessment; Role; Signal Transduction; Staging; System; Testing; Tissue Donors; Transplantation; Vascular Diseases; Vascular remodeling; Wild Type Mouse; angiogenesis; arterial remodeling; beta-Galactosidase; cardiovascular disorder risk; cardiovascular risk factor; chemokine; feeding; injured; intima media; monocyte; overexpression; research study

DESCRIPTION (provided by applicant): Adipose tissue surrounding the great vessels [perivascular (PV) adipose tissue, or PVAT] expands during obesity, is highly inflamed and correlates with coronary plaque burden and increased cardiovascular (CV) risk. A consensus is emerging that PVAT is a cause of CV disease, but direct proof is lacking. Demonstrating a pathogenic role for PVAT challenges the current paradigm that CV disease originates primarily at the intima and provides a new target for assessment and treatment of CV disease. Our laboratory has developed a robust model of PVAT transplantation to the mouse carotid artery to determine its role in eliciting vascular pathology and the mechanisms whereby PVAT interacts with metabolic factors, chemokines, inflammatory cells and the blood vessel wall. PVAT transplantation in the setting of high fat diet dramatically enhanced wire injury- induced neointimal formation and atherosclerosis, and increased adventitial inflammation and angiogenesis, providing direct evidence that PVAT plays a pathogenic role in CVD. Moreover, preliminary data suggest that transplanting PVAT from mice lacking the chemokine MCP-1 attenuates neointimal formation, consistent with pleiotropic effects of MCP-1 to promote vascular remodeling. In addition, angiotensin II (AngII) is upregulated in adipose tissue during high fat feeding and promotes adventitial remodeling and inflammation. Our central hypothesis is that PVAT synergizes with high-fat diet and AngII to enhance arterial remodeling and atherosclerosis, in part through secretion of MCP-1. To test this hypothesis, we propose three specific aims. Aim 1 will test the hypothesis that high-fat diet and AngII synergize with PVAT to enhance arterial remodeling and atherosclerosis, using PVAT from wild-type mice or AngII receptor type-1a (AT1a) knockout mice. Aim 2 will test the hypothesis that stromal-derived factor 1¿ (SDF-1¿), which increases in the intima and media soon after wire injury, is requisite for "inside-out" molecular crosstalk leading to enhanced arterial remodeling by PVAT. Aim 3 will test the hypothesis that MCP-1 secretion by PVAT is requisite for "outside-in" molecular crosstalk leading to enhanced arterial remodeling and atherosclerosis by PVAT. Using PVAT from wild-type or MCP-1 knockout mice, we will investigate an interactive role of AngII with MCP-1 in these experiments. The proposed studies are expected to provide direct evidence of a pathogenic role of PVAT in CVD, to define interactions between PVAT, high-fat diet and AngII, and to address putative molecular mechanisms of crosstalk between the blood vessel wall and PVAT. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the role of fat that surround blood vessels also known as perivascular adipose tissue, or PVAT) in causing vascular disease. We provide evidence that the inside of the blood vessel (intima) communicates with the PVAT when the artery is injured, leading to increased obstruction of the blood vessel. We plan to determine what mediates this communication system and how it is perturbed in the setting of high fat diet.

描述（由申请方提供）：肥胖期间大血管周围的脂肪组织[血管周围（PV）脂肪组织，或PVAT]扩张，高度发炎，与冠状动脉斑块负荷和心血管（CV）风险增加相关。一个共识正在形成，即PVAT是CV疾病的一个原因，但缺乏直接证据。证明PVAT的致病作用挑战了当前CV疾病主要起源于内膜的范式，并为CV疾病的评估和治疗提供了新的靶点。 我们的实验室已经开发了一个强大的模型PVAT移植到小鼠颈动脉，以确定其在引发血管病理和机制，PVAT与代谢因子，趋化因子，炎症细胞和血管壁相互作用的作用。在高脂饮食的情况下，PVAT移植显著增强了导丝损伤诱导的新生内膜形成和动脉粥样硬化，并增加了外膜炎症和血管生成，提供了PVAT在CVD中起致病作用的直接证据。此外，初步数据表明，移植PVAT缺乏趋化因子MCP-1的小鼠减弱新生内膜形成，与MCP-1的多效性作用，以促进血管重塑一致。此外，血管紧张素II（AngII）在高脂肪喂养期间在脂肪组织中上调，并促进外膜重塑和炎症。我们的中心假设是PVAT与高脂饮食和AngII协同作用，部分通过分泌MCP-1来增强动脉重塑和动脉粥样硬化。为了验证这一假设，我们提出了三个具体目标。目的1将使用来自野生型小鼠或AngII受体类型-1a（AT 1a）敲除小鼠的PVAT来验证高脂饮食和AngII与PVAT协同作用以增强动脉重塑和动脉粥样硬化的假设。目的2将检验以下假设：基质衍生因子1（SDF-1）在导丝损伤后不久在内膜和中膜中增加，是导致PVAT增强动脉重塑的“由内而外”分子串扰所必需的。目的3将检验以下假设：PVAT分泌MCP-1是导致PVAT增强的动脉重塑和动脉粥样硬化的“由外向内”分子串扰所必需的。使用来自野生型或MCP-1敲除小鼠的PVAT，我们将在这些实验中研究AngII与MCP-1的相互作用。预计拟议的研究将提供PVAT在CVD中的致病作用的直接证据，以确定PVAT，高脂饮食和AngII之间的相互作用，并解决血管壁和PVAT之间的串扰的假定分子机制。 公共卫生相关性：这项研究的目的是确定血管周围的脂肪（也称为血管周围脂肪组织，或PVAT）在引起血管疾病中的作用。 我们提供的证据表明，当动脉受伤时，血管内部（内膜）与PVAT连通，导致血管阻塞增加。 我们计划确定是什么介导了这个通信系统，以及它是如何在高脂肪饮食的设置扰动。