补体介导的血管外周脂联素表达调控参与高血压血管损伤的机制研究

Perivascular adipose tissue (PVAT), long assumed to be nothing more than vessel-supporting connective tissue, is now understood to be highly metabolically active and produced large numbers of substances that could influence the circulation both by paracrine and by endocrine effects in vascular health and disease. Our previous studies have demonstrated that the expression of complement C3 significantly increased in the PVAT of hypertensive mice. Activated complement peptide C5a induced inflammatory factors expression in the perivascular macrophages, which contributes to hypertension-related vascular inflammation. Our recently work also showed that PVAT-derived Adiponectin, an anti-inflammatory adipocytokine, was decreased in hypertensive mice. Based on these findings, we hypothesized that Complement-mediated macrophage activation regulated Adiponectin expression in perivascular adipocytes, which contributed to hypertensive vascular injury. Thus the present study aimed to further explored: 1) The role of PVAT-derived Adiponectin in hypertension-related vascular injury; 2) Complement-mediated macrophage activation inhibits Adiponectin expression in the adipocytes; 3) The Complement-Adiponectin pathway-mediated interaction of perivascular macrophages and adipocytes regulates vascular contraction and relaxation functions; 4) To explain the molecular mechanism of Complement-Adiponectin pathway-mediated perivascular inflammation in hypertensive vascular injury by using Complement and Adiponectin knockout mice. Our findings will provide potential the therapic target for hypertension-related vascular injury.

越来越多的证据表明血管外周脂肪组织通过分泌活性介质参与血管生物学功能的调控。我们以往的研究证实高血压动物模型血管外周脂肪组织合成分泌大量补体C3，补体激活产生的活性介质C5a促进巨噬细胞分泌炎症因子参与血管外周脂肪组织炎症反应的调控。同时我们前期研究发现高血压小鼠血管外周抗炎性脂肪因子脂联素表达显著降低，因此我们假设补体介导的巨噬细胞活化参与血管血管外周脂联素表达调控，并进一步参与高血压血管损伤过程的调控。基于此，本项目将继续探索：1）血管外周脂肪因子脂联素在高血压血管损伤过程中的表达调控机制；2）补体通过激活巨噬细胞抑制脂联素表达分泌的细胞分子机制；3）通过补体的介导脂联素表达调控研究巨噬细胞与脂肪细胞的相互作用参与血管功能的调节；4）利用补体和脂联素敲除小鼠证实补体与脂联素的协同作用参与高血压血管损伤过程的调控。这些研究结果的取得将为防治高血压血管损伤提供潜在的干预靶点。

补体激活产生的活性介质C3a和C5a促进巨噬细胞分泌炎症因子参与血管外周脂肪组织炎症反应的调控。同时发现高血压小鼠血管外周抗炎性脂肪因子脂联素表达显著降低，因此本项目主要研究补体介导的巨噬细胞活化参与血管血管外周脂联素表达调控，并进一步参与高血压心血管损伤过程的调控。项目主要研究内容和结果包括：1）补体系统的活化参与管周脂联素的表达调控；2）补体介导的管周脂肪细胞与巨噬细胞交互作用参与心血管重构的调控过程；3）补体介导的炎症反应参与血压调节并通过分泌脂肪因子参与靶器官损伤调控。通过本项目，证实补体介导的管周脂肪因子脂联素等表达紊乱参与管周免疫微环境的改变，包括天然免疫系统的巨噬细胞以及适应性免疫的T细胞共同参与管周炎症反应的调控过程，进而参与高血压心血管损伤的调节。