JAM-A通过整合素αIIbβ3调节血小板活性在动脉内膜增生中的机制研究

腔内手术治疗动脉狭窄和闭塞，会诱发内膜增生，导致支架内再狭窄。内膜增生是血管壁慢性炎症过程，血小板在其中发挥重要作用，但机制尚未明确。我们研究发现：连接黏附分子A (JAM-A）通过整合素αIIbβ3抑制血小板活性，抑制动脉粥样硬化斑块形成，但在内膜增生中的作用未明。鉴于JAM-A是血管壁炎症和重塑的重要调节因子，推断：JAM-A也可能通过整合素αIIbβ3抑制血小板活性，抑制内膜增生。本项目拟在前期研究基础上，利用血小板JAM-A缺陷型小鼠内膜损伤模型，研究JAM-A调节血小板功能对血管炎性因子表达的影响，以及对白细胞的趋化作用；分析不同病变阶段的新生内膜面积和细胞组分，探讨血小板JAM-A在血管壁炎症和重塑中的作用机制；结合特异性拮抗剂，探讨JAM-A-Src-αIIbβ3信号通路调节血小板活性在内膜增生中的分子机制，为再狭窄的防治提供新的理论基础。

The endovascular surgery as a popular treatment to artery stenosis or occlusion triggers neointima formation and restenosis, which is a chronic inflammatory process. Platelet plays important roles in neointima formation, however, the mechanism is still unknown. It has been demonstrated that Junctional adhesion molecular A（JAM-A） through integrin αIIbβ3 suppresses platelet activities and plaque formation, which promotes this proposal about platelet-JAM-A in neointima formation. Thus, we hypothesize that platelet JAM-A may inhibit neointima formation through down-regulating platelet activities by integrin αIIbβ3. Mice with or without platelet-specific JAM-A-deficiency under an apolipoprotein e deficiency (apoe-/-) background will be used to establish wire-injury model in left carotid artery as a good model of neointima hyperplasia. During neointima pathogenesis, platelet activities under stimuli combined with specific blockers will be analyzed, including adhesion、aggregation、secretion and interactions with leukocytes on injured vessel wall. The vascular inflammation will be characterized by chemokine expression in plasma and injured vessel wall and certified by leukocyte recruitment under JAM-A-/- platelet stimulation. The molecular mechanisms of JAM-A-Src-αIIbβ3 regulating platelet activities in neointima formation will be clarified by specific blockers in above experiments. Ultimately, neointima cell composition will be characterized to illustrate whether JAM-A-/- platelets aggravate the vascular inflammation and vascular remodeling in different stages of neointima formation. This study will highlight the detrimental roles of JAM-A-Src-αIIbβ3 signaling pathway in neointima formation and restenosis, which might be used by new approaches to inhibit neointima hyperplasia.