KDM1A调控BMP2/BMPR/Smad5信号通路在脑血管Willis环动脉瘤形成和破裂中的作用机制

The Willis ring of cerebral artery is tortuous and multi-branched. Disturb flow(DF) is one of the main factors to promote the formation and rupture of cerebral aneurysm. DF, which may lead to vascular endothelial injury, can influence the expression of many genes by regulating the activity of KDM1A/LSD-1 in the endothelial cells. However, it is not clear that the expression pattern of KDM1A in the aneurysm wall and the role of the regulatory mechanism of the target genes in the pathogenesis of cerebral aneurysms. Studies have shown that the transcription of BMP2 is regulated by KDM1A. Moreover, the TGF-b/BMP signaling pathway may be involved in the formation of intracranial aneurysms. We found that the expression of KDM1A was down-regulated, but the expression of BMP2 was up-regulated in human aneurysms. It is speculated that KDM1A may be involved in the formation and rupture of cerebral aneurysms by regulating BMP2/BMPR/Smad5 signaling pathway. The project intends to explore the molecular mechanism of KDM1A regulating BMP2/BMPR/Smad5 signaling pathway in the formation and rupture of cerebral aneurysms by using a new rat model of cerebral aneurysm, human aneurysm tissue and cultured cells under simulated DF conditions.

脑动脉Willis环处血管迂曲且分支较多，血液的湍流成为促进该处脑动脉瘤形成和破裂的主要因素之一，湍流可通过调节血管内皮细胞中赖氨酸去甲基化酶1A（KDM1A/LSD-1）的活性进而调控多种基因的表达，参与血管内皮损伤过程。然而，动脉瘤壁内KDM1A的表达模式以及对靶基因的调控机制在脑动脉瘤的发生发展中所起的作用尚不清楚。研究显示骨形态蛋白BMP2的转录受KDM1A的调控；并且，TGF-b/BMP信号通路可能参与了颅内动脉瘤的形成。我们前期实验发现人体动脉瘤组织中KDM1A表达下调，而BMP2的表达上调。进而推测，KDM1A可能通过调控BMP2/BMPR/Smad5信号通路参与脑动脉瘤的形成和破裂。本项目拟采用一种新的大鼠脑动脉瘤诱导模型、人体动脉瘤组织以及模拟湍流条件下培养细胞等三个角度探索KDM1A调控BMP2/BMPR/Smad5信号通路在脑动脉瘤形成和破裂过程中的分子机制。

脑动脉瘤是发病率、致残率和致死率均较高的脑血管疾病，但是其发病机制目前尚不明确。动脉瘤壁内弹力层断裂缺失、炎症细胞浸润和动脉中层血管平滑肌细胞（VSMCs）功能失调或缺失等病理现象似乎是脑动脉瘤的共同特征，我们通过该课题重点研究了VSMCs的功能失调在动脉瘤形成中所起的作用。VSMC的表型转化（收缩型向合成型转化）是其功能失调的关键性起始步骤。因此，如果能预防甚至逆转VSMCs表型转化，即可在早期遏制疾病的发生、发展。对VSMCs表型转化的机理研究发现，其主要由多种生长因子（例如：血管紧张素-II、bFGF、TGF-β及PDGF等）和机械性刺激所诱发，并通过多种信号通路将刺激信号传导至细胞核内，最终引起平滑肌细胞分化标志基因表达的改变。我们前期实验发现人体动脉瘤组织中KDM1A表达下调，而BMP2的表达上调。进而推测，KDM1A可能通过调控BMP2/BMPR/Smad5信号通路参与脑动脉瘤的形成和破裂。然而，KDM1A在大鼠颈动脉损伤模型的VSMCs中表达增强，并通过调控靶基因BMP2的表达以及BMP2/BMPR/SMADs通路调节VSMCs的细胞功能和表型，抑制KDM1A的作用后可抑制VSMCs的增殖和迁移，对动脉损伤修复有积极作用。这种反向表达的现象提示了KDM1A在炎症诱导的VSMC功能失调的不同病理阶段中所起的作用具有时相性，深入研究KDM1A的相关作用分子及其机制显得尤为重要。在大鼠的动脉壁机械损伤模型中我们发现，随着VSMC的过度增生，RNA结合蛋白HuR（RBP-HuR）的表达较对照组呈现增强趋势，通过转录组测序技术分析预测了KDM1A是HuR的靶基因之一，并通过小鼠VSMC中elavl1（HuR）沉默质粒转染等实验验证了这一预测。通过该课题的研究，初步明确了KDM1A在VSMC的亚型转换及功能失调中起到重要作用，有望通过进一步的深入研究，揭示其分子调控网络及具体机制。目前脑动脉瘤在病理形态发生前尚无有效的筛查手段，希望通过全面深入的研究早日弥补这一空白。