Perivascular adipose tissue and vascular remodeling

描述(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，高度炎症，与冠状动脉斑块负担和心血管(CV)风险增加相关。PVAT是心血管疾病的原因之一，这一共识正在形成，但缺乏直接证据。PVAT的致病作用挑战了心血管疾病主要起源于内膜的现有模式，并为心血管疾病的评估和治疗提供了一个新的靶点。本实验室建立了PVAT移植到小鼠颈动脉的模型，以确定PVAT在诱发血管病变中的作用，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。在高脂饮食环境下移植PVAT可显著增加血管内膜损伤诱导的新生内膜形成和动脉粥样硬化，增加外膜炎症和血管生成，为PVAT在心血管疾病中的致病作用提供了直接证据。此外，初步数据表明，从缺乏趋化因子MCP-1的小鼠移植PVAT可以减少新生内膜形成，这与MCP-1促进血管重塑的多效性作用是一致的。此外，血管紧张素II(AngII)在高脂饮食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与高脂饮食和血管紧张素Ⅱ协同作用，部分通过分泌MCP-1来增强动脉重构和动脉粥样硬化。为了检验这一假设，我们提出了三个具体目标。目的1利用野生型小鼠或血管紧张素Ⅱ受体1a(AT1a)基因敲除小鼠的PVAT，验证高脂饮食和血管紧张素转换酶与PVAT协同增强动脉重塑和动脉粥样硬化的假设。目的2验证基质衍生因子-1(SDF-1)是PVAT增强动脉重塑的“内向外”分子串扰的必要条件。目的3验证PVAT分泌MCP-1是导致PVAT增强动脉重塑和动脉粥样硬化的分子串扰所必需的假说。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在这些实验中的相互作用。这些拟议的研究有望提供PVAT在CVD中的致病作用的直接证据，确定PVAT、高脂饮食和血管紧张素转换酶之间的相互作用，并解决血管壁和PVAT之间可能存在的串扰的分子机制。

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.