巨噬细胞调控管周脂肪及干细胞分化在血管损伤中的机制研究

Macrophages are essential component of the immune system and macrophage-mediated inflammation is involved in the regulation of vascular injury. Perivascular adipose tissue (PVAT) plays a notable role in maintaining vascular homeostasis. However, it remains unclear how crosstalk between macrophages and PVAT affects vascular injury. Our previous studies have demonstrated that macrophage activation induces dysfunction of PVAT and PVAT-derived stem cell (PVASC) differentiation. Based on these results, we aim to investigate whether and how macrophages regulate PVASC differentiation, perivascular white/brown adipocyte differentiation, and then affect related vascular injury. We will study: 1) The origin of PVASCs and their multipledifferentiation capacity induced by hypertension or high-fat diet (HFD); 2) The interplay between macrophage polarization and PVAT dysfunction in the regulation of vascular remodeling; 3) The mechanism of macrophage-mediated PVASC differentiation, PVAT dysfunction, and dysregulation of vascular homeostasis; 4) Identification of new targets utilizing high-throughput lipid metabolomics and proteomics and integrative omic approaches, and screening for small molecule compounds with protective effects on vascular injury. The outcome of these studies may identify novel therapeutic targets and strategies for intervention and prevention of vascular diseases.

巨噬细胞作为免疫系统的重要细胞成分，介导的炎症反应参与血管损伤过程已得到广泛认可；而管周脂肪组织作为一种新认识的管壁结构在血管稳态中的作用亦被关注，但两者交互作用参与血管损伤的机制尚不清楚。我们前期研究发现各种调节因子介导的巨噬细胞激活影响管周脂肪功能紊乱和管周干细胞分化异常。本项目基于上述的研究基础，深入阐明巨噬细胞调节管周干细胞分化、脂肪细胞白色/棕色化及其在血管损伤中的作用机制。主要研究：1）鉴定高血压、高脂等诱导血管损伤时管周干细胞的起源及分化多潜能性；2）危险因素介导的巨噬细胞极化与管周脂肪的双向调节在血管重塑中的作用和机制；3）巨噬细胞调节管周干细胞分化和管周脂肪功能紊乱与血管稳态失衡；4）利用高通量脂质代谢组学和蛋白质修饰组学方法，鉴定巨噬细胞上述作用的新靶点，并筛选具有修复血管损伤功能的活性小分子。这些研究结果将为防治危险因素导致的血管损伤提供潜在的干预靶点和策略。

巨噬细胞作为免疫系统的重要细胞成分，介导的炎症反应参与血管损伤过程已得到广泛认可；而管周脂肪组织作为一种新认识的管壁结构在血管稳态中的作用亦被关注，但两者交互作用参与血管损伤的机制尚不清楚。我们前期研究发现各种调节因子介导的巨噬细胞激活影响管周脂肪功能紊乱和管周干细胞分化异常。该项目在高平进、王宪、段胜仲三位课题组长的共同努力下，按计划执行情况，鉴定了多种危险因素（高血压等）引起血管损伤时管周原位干细胞的分化多潜能性；发现巨噬细胞与管周脂肪双向调节在血管重塑中的作用和机制；发现巨噬细胞与管壁细胞相互作用参与血管稳态失衡的机制；最后利用高通量代谢组学方法，发掘了巨噬细胞调控血管损伤的新靶点（如HIF-1α、IFN-γ、PDGF-D、NCoR1、IRE1α），并筛选出干预神经酰胺和活性磷脂等活性脂质小分子对血管重塑的改善作用。以上研究为防治心血管疾病乃至寻找新的治疗策略与干预靶点提供了理论基础。