补体介导的巨噬细胞活化参与衰老小鼠下肢缺血后血管新生调控的机制研究

Angiogenesis is the basic condition for the regeneration of tissue injury, but aging prevents the process of angiogenesis after tissue injury. Our preliminary study showed that the expression of complement3（C3）was increased with the infiltration of macrophages in the aging mice after lower limb ischemia, and it improve the angiogenesis when we knockouted C3 from aging mice. Our previous studies demonstrated that C3 is involved in the regulation of macrophage polarization. Macrophages could secrete angiogenic factors involved in the regulation of angiogenesis, and the polarization of macrophages is involved in the regulation of sFlt1 and other angiogenic factors. Therefore, we hypothesized that aging activation mediated pathways of complement by C3, and it inhibits angiogenesis by promoting macrophage sFlt1 after lower limb ischemia. Based on the assumption, the main research contents are as follows: (1) senescence induced complement activation of angiogenesis in lower limb ischemia. (2) C3 mediated macrophage activation is involved in the regulation of angiogenesis (3) C3 induced upregulation of sFlt1 is involved in the regulation of angiogenesis in macrophages. (4) Using the humanized mouse model of the immune system to confirm the involvement of C3a mediated macrophage activation in angiogenesis. This project will provide a theoretical basis for new intervention target to treatment of lower limb ischemic disease by the C3 mediated macrophage activation.

血管新生是组织损伤后再生的基本条件，但是衰老阻碍了组织损伤后的血管新生过程。我们预初研究发现衰老小鼠下肢缺血损伤后补体C3表达增加并伴随巨噬细胞浸润，补体C3敲除改善衰老小鼠的血管新生。我们以往研究证实C3参与巨噬细胞极化的调控。巨噬细胞能够分泌血管生成调节因子参与血管新生过程的调控，而巨噬细胞的极化参与sFlt1等血管生成因子的调控。因此我们提出研究假设：衰老激活C3介导的补体途径，并通过促进巨噬细胞分泌sFlt1抑制下肢缺血后的血管新生，并基于此假设主要研究：（1）衰老诱导补体活化参与下肢缺血后血管新生。（2）C3介导的巨噬细胞的活化参与血管新生的调控。（3）C3诱导的sFlt1的表达上调参与巨噬细胞的血管新生调控作用。（4）用免疫系统人源化小鼠模型证实C3a介导的巨噬细胞的活化参与血管新生。本项目将为补体C3介导的巨噬细胞活化为新干预靶点治疗衰老相关下肢缺血疾病提供理论依据。

血管新生是组织损伤后再生的基本条件，但是衰老阻碍了组织损伤后的血管新生过程。我们研究发现衰老激活C3介导的补体途径，证实C3参与巨噬细胞极化的调控并通过促进巨噬细胞分泌sFlt1抑制下肢缺血后的血管新生，衰老小鼠下肢缺血损伤后补体C3表达增加并伴随巨噬细胞浸润，补体C3敲除改善衰老小鼠的血管新生；巨噬细胞能够分泌血管生成调节因子参与血管新生过程的调控，而巨噬细胞的极化参与sFlt1等血管生成因子的调控；衰老诱导补体活化参与下肢缺血后血管新生。C3介导的巨噬细胞的活化参与血管新生的调控。C3诱导的sFlt1的表达上调参与巨噬细胞的血管新生调控作用。用免疫系统人源化小鼠模型证实C3a介导的巨噬细胞的活化参与血管新生。本项目将为补体C3介导的巨噬细胞活化为新干预靶点治疗衰老相关下肢缺血疾病提供理论依据。