乙醛脱氢酶2调节血管外膜干细胞分化进而促进移植静脉血管内膜增生的机制研究

Autologous vein grafts remain the only surgical alternative for many types of vascular reconstruction, but the patency rate is still limited because of neointima formation within the grafted vessels. Previous work has mostly focused on the putative roles of cellular players that were derived from either the intima or media. In the recent studies, adventitial stem/progenitor cells have been proved to participate in neointimal formation in inflammatory microenvironment of vein grafts. After transplantation, the adventitial stem/progenitor cells of vein grafts are within ischemia, hypoxia and inflammatory microenvironment. However, the environmental regulatory mechanism is essentially unclear. Our previous data showed a vital role of aldehyde dehydrogenase-2 (ALDH2) in microenvironment homeostasis after ischemia. We have found that ALDH2 could enhance the differentiation of adventitial Sca-1+ cells to smooth muscle cells (SMCs) and ALDH2 deletion could ameliorate vein graft neointimal hyperplasia. Based on these previous findings, we hypothesized that ALDH2 promote vein graft neointimal hyperplasia via facilitating adventitial stem/progenitor cells differentiation surrounded by inflammatory and hypoxia microenvironment. To verify it, we will use ALDH2 knockout Sca-1+ cells，macrophages and mice to explore metabolic and differential characteristics of Sca-1+ cells and macrophages and associated reactive pathway molecules among them. This study focus on identifying the effects of ALDH2 on adventitial Sca-1+ cells differentiation and proliferation followed by vein graft neointimal hyperplasia. The findings might provide a novel therapeutic target for preserving vein graft patency.

自体静脉移植广泛应用于临床血管重建，但因为移植血管新生内膜增生，移植血管的远期通畅率仍有限。以往关于新生内膜增生狭窄的研究主要集中于血管内膜或中膜细胞。最近研究发现，移植血管外膜存在的干/祖细胞可参与血管壁内炎症微环境形成、促进新生内膜增生，但机制不详。我们以往研究表明乙醛脱氢酶2（ALDH2）对于维持缺血后微环境的动态平衡发挥重要作用，预实验又发现ALDH2能促进血管外膜干细胞（Sca-1+细胞）分化为平滑肌细胞，且ALDH2缺失能够减轻桥血管狭窄。由此我们推测：ALDH2通过促进处于炎性缺氧微环境中血管外膜干/祖细胞的分化增殖，进而加速移植静脉内膜增生性狭窄。为求验证，我们拟运用ALDH2基因敲除小鼠，从Sca-1+细胞、巨噬细胞交互作用等角度深入探究代谢模式及分化对微环境的影响。旨在明确ALDH2调控血管外膜干细胞等的分化和增殖导致桥血管狭窄的分子通路，为维持桥血管通畅提供有效靶点。

随着社会经济的发展，国民生活方式发生了深刻的变化，中国心血管病危险因素流行趋势明显，导致了心血管病的发病人数持续增加。目前，心血管病死亡占城乡居民总死亡原因的首位。冠状动脉旁路移植术是内科药物治疗不佳和多支冠状动脉弥漫性狭窄的冠心病患者的优先治疗手段，其可有效改善患者心脏供血缓解患者症状。自体大隐静脉是冠状动脉旁路移植术中最常用的移植材料。然而术后相当一部分患者出现静脉血管桥再狭窄。乙醛脱氢酶2（aldehyde dehydrogenase，ALDH2）位于线粒体，是体内醛类氧化关键酶，近年已被证实为内源性心脏保护因子，在心梗后心衰、心脏缺血再灌注损伤、酒精性心肌病等病理过程中发挥重要保护作用。我们发现，巨噬细胞的存在能够增加血管外膜干细胞的迁移和分化， 而ALDH2敲除显著延缓和减轻这一系列病理生理过程。我们通过建立小鼠静脉移植模型、桥血管外膜细胞的培养和Sca-1+ 细胞的分离提取、检测ALDH2缺失对巨噬细胞，外膜干细胞，平滑肌细胞的迁移能力的影响，最终初步证实ALDH2影响巨噬细胞的迁移及分化，从而影响血管外膜干细胞及血管平滑肌细胞的活性，最终影响移植静脉的新生内膜的活性及搭桥静脉的成活率。研究成果将进一步理解静脉移植新生内膜形成的病理机制，并为临床静脉移植相关疾病的治疗和预防提供新的治疗靶点。