Perivascular adipose tissue and vascular remodeling

血管周围脂肪组织和血管重塑

基本信息

批准号：
9063172
负责人：
Neal L Weintraub
金额：
$ 39.9万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-13 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063172
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 High Fat Diet 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 pleiotropism research study western diet

项目摘要

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（由适用提供）：在肥胖期间，巨大血管[周围（PV）脂肪组织或PVAT]周围的脂肪组织高度发炎，与冠状动脉斑块伯恩（Burnen）和心血管增加（CV）风险相关。一致认为PVAT是CV疾病的原因，但缺乏直接证明。证明PVAT的致病作用挑战了CV疾病主要起源于Intima的当前范式，并为CV疾病评估和治疗提供了新的目标。我们的实验室已经开发了一种强大的PVAT移植模型向小鼠颈动脉移植，以确定其在引起血管病理学的作用以及PVAT与代谢因子，趋化因子，炎症细胞和血管壁相互作用的机制。高脂饮食中的PVAT移植显着增强了电线损伤诱导的新源性形成和动脉粥样硬化，并增加了晚期感染和血管生成，提供了直接证据表明PVAT在CVD中起致病作用。此外，初步数据表明，缺乏趋化因子MCP-1的小鼠的移植PVAT减弱了新的形成，这与MCP-1的多效性作用一致，以促进血管重塑。此外，在高脂肪进食期间，血管紧张素II（AngII）在脂肪组织中进行了更新，并促进了促进重塑和炎症。我们的中心假设是，PVAT与高脂饮食和ANGII协同作用，以增强动脉重塑和ANGII，以增强动脉重塑和ANGII，以通过MCP-1分泌进行分泌。为了检验这一假设，我们提出了三个具体目标。 AIM 1将测试使用野生型小鼠或Angii受体1A型（AT1A）敲除小鼠的PVAT，即高脂饮食和AngII与PVAT协同增强动脉重塑和动脉粥样硬化。 AIM 2将检验以下假设：基质衍生的因子1（SDF-1）在线损伤后不久在内膜和培养基中增加，这是“内部”分子串扰的必要条件，从而导致PVAT增强动脉重塑。 AIM 3将检验以下假设：PVAT的MCP-1分泌是“外部”分子串扰的必需，从而导致PVAT的动脉重塑和动脉粥样硬化增强。使用野生型或MCP-1基因敲除小鼠的PVAT，我们将研究Angii与MCP-1在这些实验中的互动作用。拟议的研究有望提供PVAT在CVD中的致病作用的直接证据，以定义PVAT，高脂饮食和Angii之间的相互作用，并解决血管壁和PVAT之间串扰的假定分子机制。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153.

DOI：
10.1371/journal.pone.0124059
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Baban B;Liu JY;Qin X;Weintraub NL;Mozaffari MS
通讯作者：
Mozaffari MS

Disruption of endothelial Pfkfb3 ameliorates diet-induced murine insulin resistance.

DOI：
10.1530/joe-20-0524
发表时间：
2021-06
期刊：
The Journal of endocrinology
影响因子：
0
作者：
Qiuhua Yang;Jiean Xu;Qian Ma;Zhiping Liu;Yaqi Zhou;Yongfeng Cai;Xiaoxiao Mao;D. Stepp;Neal Weintraub;D. Fulton;Mei Hong;Yuqing Huo
通讯作者：
Qiuhua Yang;Jiean Xu;Qian Ma;Zhiping Liu;Yaqi Zhou;Yongfeng Cai;Xiaoxiao Mao;D. Stepp;Neal Weintraub;D. Fulton;Mei Hong;Yuqing Huo

The Role of Perivascular Adipose Tissue in Non-atherosclerotic Vascular Disease.