HIF2a-CXCL1-CXCR2轴在血管平滑肌细胞与单核细胞交互作用及腹主动脉瘤发生发展中的作用研究

Interplay between vascular smooth muscle cells (VSMC) and monocyte-derived macrophages play a key role in the development of remodeling-related cardiovascular diseases, such as abdominal aortic aneurysms (AAA). However, how monocytes is recruited by VSMCs during AAA remains elusive. We previously found that hypoxic niche exists in VSMCs from Angiotensin II-induced AAA in apoE-null mice and from human AAA samples, accompanied by HIF2a activation. Preliminary study showed that VSMC-specific disruption of HIF2a in apoE-null mice significantly reduced the secretion of chemokine CXCL1 in VSMCs, dramatically inhibited the recruitment of monocytes/macrophages. VSMC-specific HIF2a-deficient apoE-null mice exhibited less AAA formation and rupture. Bioinformatics analysis indicated that CXCL1 might be a HIF2a target gene. Hence, we hypothesize that HIF2a-CXCL1-CXCR2 axis may serve as an important link between VSMC and macrophages to accelerate AAA development, and small molecules targeting this axis may be a potential therapeutic target for AAA. This project will not only enhance our understanding for the pathophysiology of AAA, but also provide novel approaches for the prevention and treatment of AAA.

血管平滑肌细胞（VSMC）与单核巨噬细胞交互作用在腹主动脉瘤（AAA）等血管重塑性疾病中起重要作用，然而其联系纽带并不清楚。我们前期研究发现，血管紧张素II诱导的apoE-/-小鼠AAA模型及人AAA标本局部VSMC中存在低氧，且HIF2a被明显激活。特异性敲除VSMC中HIF2a可明显抑制VSMC分泌趋化因子CXCL1，减少AngII诱导的巨噬细胞募集，并显著抑制AAA发生发展。进一步生物信息学分析显示，CXCL1启动子上存在HIF2a结合位点。因而我们提出科学假说：AngII等可激活VSMC中HIF2a，通过其靶基因CXCL1，与单核巨噬细胞CXCR2相互作用，促进单核巨噬细胞募集，加重血管局部炎症，促进AAA发生发展；通过小分子化合物干预HIF2a-CXCL1-CXCR2轴，可能延缓AAA发生发展。本项目的实施将不仅丰富血管重塑性疾病AAA的发生机制，对该类疾病的防治亦具有重大意义。

腹主动脉瘤（AAA）是受多因素影响的具有潜在破裂风险的主动脉病理性扩张性疾病，其药物防治手段依然匮乏，因而迫切需要深入解析其机制，以期为临床提供潜在治疗靶点。本项目为依托血管稳态与重构的调控机制重大研究计划，探究了血管平滑肌细胞（VSMC）与单核细胞交互作用的分子机制及其在腹主动脉瘤进程中的贡献。结果显示，血管紧张素II等可激活VSMC中低氧诱导因子2a（HIF2a），促进VSMC向致炎表型转化，增加HIF2a下游靶基因CXCL1表达，通过与单核细胞及中性粒细胞表面CXCR2相互作用，促进致炎性单核细胞及中性粒细胞向血管局部募集，加重血管局部炎症，加速AAA的进程；招募到血管局部的中性粒细胞，可通过释放细胞外诱捕网（NETs），促进VSMC凋亡，加速AAA的破裂；阻断HIF2a-CXCL1-CXCR2轴可减少AAA的发生及破裂，而抑制NETs对AAA的形成没有显著影响，但可降低AAA的破裂率。上述结果从动物、细胞及分子水平揭示了HIF2a可作为VSMC与致炎性免疫细胞之间相互作用的联系纽带，并初步尝试了以HIF2a-CXCL1-CXCR2轴及NETs作为AAA治疗靶点的可行性，这不仅加深了我们对AAA发病机制的理解，也对发展血管重塑性疾病的新干预和治疗手段具有重要意义。