Perivascular adipose tissue and vascular remodeling

血管周围脂肪组织和血管重塑

• 批准号: 8686066
• 负责人: Neal L Weintraub
• 金额: $ 40.88万
• 依托单位: AUGUSTA UNIVERSITY
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686066
• 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.

描述（由申请人提供）：大血管周围的脂肪组织[血管周围（PV）脂肪组织，或PVAT]在肥胖期间扩张，高度发炎，并且与冠状动脉斑块负荷和心血管（CV）风险增加相关。 PVAT 是 CV 疾病的病因，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，并为评估和治疗提供了新的靶点。我们的实验室开发了一种强大的小鼠颈动脉PVAT移植模型，以确定其在引发血管病理学中的作用以及PVAT与代谢因子、趋化因子、炎症细胞和PVAT移植的相互作用的机制。高脂肪饮食的设置显着增强了线损伤诱导的新内膜形成和动脉粥样硬化，并增加了外膜炎症和血管生成，这提供了PVAT在CVD中发挥致病作用的直接证据。初步数据表明，移植缺乏趋化因子 MCP-1 的小鼠的 PVAT 会减弱新内膜形成，这与 MCP-1 促进血管重塑的多效作用一致。此外，高脂肪喂养期间脂肪组织中血管紧张素 II (AngII) 上调并促进血管重塑。我们的中心假设是，PVAT 与高脂肪饮食和 AngII 协同作用，可增强动脉重塑和炎症。动脉粥样硬化，部分通过 MCP-1 的分泌 为了检验这一假设，我们提出了三个具体目标，即使用来自野生动物的 PVAT 来检验高脂肪饮食和 AngII 与 PVAT 协同作用以增强动脉重塑和动脉粥样硬化的假设。 Aim 2 型小鼠或 AngII 受体 1a 型 (AT1a) 敲除小鼠将测试基质衍生因子 1¿ (SDF-1¿) 在内膜和中膜损伤后不久就会增加，这是“由内而外”的分子串扰导致 PVAT 增强动脉重塑的必要条件。目的 3 将检验 PVAT 分泌 MCP-1 的假设。使用来自野生型或 MCP-1 敲除的 PVAT 是“由外向内”分子串扰导致增强动脉重塑和动脉粥样硬化的必要条件。小鼠，我们将在这些实验中研究 AngII 与 MCP-1 的相互作用作用。拟议的研究预计将提供 PVAT 在 CVD 中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。解决血管壁和 PVAT 之间串扰的假定分子机制。