Abstract：
Vascular smooth muscle cells (vSMCs) play a crucial role in both the pathogenesis of Aneurysms and Dissections of the ascending thoracic aorta (TAAD) in humans and in the associated adaptive compensatory responses, since thrombosis and inflammatory processes are absent in the majority of cases. Aneurysms and dissections share numerous characteristics, including aetiologies and histopathological alterations: vSMC disappearance, medial areas of mucoid degeneration, and extracellular matrix (ECM) breakdown. Three aetiologies predominate in TAAD in humans: (i) genetic causes in heritable familial forms, (ii) an association with bicuspid aortic valves, and (iii) a sporadic degenerative form linked to the aortic aging process. Genetic forms include mutations in vSMC genes encoding for molecules of the ECM or the TGF-β pathways, or participating in vSMC tone. On the other hand, aneurysms and dissections, whatever their aetiologies, are characterized by an increase in wall permeability leading to transmural advection of plasma proteins which could interact with vSMCs and ECM components. In this context, blood-borne plasminogen appears to play an important role, because its outward convection through the wall is increased in TAAD, and it could be converted to active plasmin at the vSMC membrane. Active plasmin can induce vSMC disappearance, proteolysis of adhesive proteins, activation of MMPs and release of TGF-β from its ECM storage sites. Conversely, vSMCs could respond to aneurysmal biomechanical and proteolytic injury by an epigenetic phenotypic switch, including constitutional overexpression and nuclear translocation of Smad2 and an increase in antiprotease and ECM protein synthesis. In contrast, such an epigenetic phenomenon is not observed in dissections. In this context, dysfunction of proteins involved in vSMC tone are interesting to study, particularly in interaction with plasma protein transport through the wall and TGF-β activation, to establish the relationship between these dysfunctions and ECM proteolysis.
摘要：
血管平滑肌细胞（vSMC）在人类动脉瘤和升胸主动脉夹层（TAAD）的发病机理以及相关的适应性代偿反应中起着至关重要的作用。因为在大多数情况下没有血栓形成和炎症过程。动脉瘤和夹层有许多共同的特征，包括病因和组织病理学改变：vSMC消失，粘液样变性的内侧区域，和细胞外基质（ECM）分解。三种病因在人类TAAD中占主导地位：（i）可遗传家族形式的遗传原因，(ii)与二叶主动脉瓣的联合，和（iii）与主动脉衰老过程有关的零星退行性形式。遗传形式包括编码ECM或TGF-β途径分子的vSMC基因中的突变，或参与vSMC音调。另一方面,动脉瘤和夹层，不管他们的病因是什么，其特征在于壁通透性增加，导致血浆蛋白的透壁平流，这些蛋白可以与vSMC和ECM成分相互作用。在这种情况下，血源性纤溶酶原似乎起着重要作用，因为它通过墙壁的向外对流在TAAD中增加，它可以在vSMC膜上转化为活性纤溶酶。活性纤溶酶可诱导vSMC消失，粘附蛋白的蛋白水解，MMP的激活和TGF-β从其ECM储存位点的释放。相反，vSMC可以通过表观遗传表型开关对动脉瘤生物力学和蛋白水解损伤做出反应，包括Smad2的结构性过表达和核易位以及抗蛋白酶和ECM蛋白合成的增加。相比之下,在解剖中没有观察到这种表观遗传现象。在这种情况下，参与vSMC音调的蛋白质的功能障碍是有趣的研究，特别是在与血浆蛋白通过壁转运和TGF-β激活的相互作用中，建立这些功能障碍与ECM蛋白水解之间的关系。
