Perivascular adipose tissue and vascular remodeling

描述（由申请人提供）：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，高度炎症，与冠状动脉斑块负担和心血管（CV）风险增加相关。一种共识正在形成，即PVAT是CV疾病的一个原因，但缺乏直接证据。证明PVAT的致病作用挑战了目前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PVAT移植到小鼠颈动脉模型，以确定其在引发血管病理中的作用，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。在高脂肪饮食环境下，PVAT移植显著增强了丝损伤诱导的新内膜形成和动脉粥样硬化，增加了外膜炎症和血管生成，为PVAT在CVD中起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的小鼠身上移植PVAT会减弱新内膜的形成，这与MCP-1促进血管重塑的多效性作用一致。此外，在高脂肪喂养过程中，血管紧张素II （AngII）在脂肪组织中上调，促进外膜重塑和炎症。我们的中心假设是PVAT与高脂肪饮食和AngII协同作用，部分通过MCP-1的分泌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。Aim 1将使用野生型小鼠或AngII受体1a型（AT1a）敲除小鼠的PVAT来验证高脂肪饮食和AngII与PVAT协同增强动脉重塑和动脉粥样硬化的假设。目的2将验证基质衍生因子1¿（SDF-1¿）的假设，该因子在导线损伤后内膜和介质中迅速增加，是“内向外”分子串扰导致PVAT增强动脉重塑所必需的。目的3将验证PVAT分泌MCP-1是“由外而内”的分子串扰导致PVAT增强动脉重塑和动脉粥样硬化所必需的假设。使用野生型或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。这些拟议的研究有望为PVAT在CVD中的致病作用提供直接证据，确定PVAT、高脂肪饮食和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。

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.