Matricellular protein CCN3 in vascular homeostasis

总结 主动脉内稳态对血管健康至关重要。血管内皮是一个重要的器官， 对正常血管生理学至关重要;当失调时，它成为发病机制中的关键因素 各种血管疾病的症状越来越多的证据表明，内皮细胞（ECs）发挥着重要作用， 在胸主动脉瘤和夹层（TAAD）的发展和进展中的作用未得到充分认识。 最值得注意的是，受损的屏障完整性被认为是TAA发展的前兆。 我们实验室的工作使人们认识到，蜂窝通信网络（CCN）的一个成员 基因家族CCN 3是血管健康的重要调节因子。然而，精确的生理 CCN 3在体内的作用以及负责CCN 3作用的基本机制在很大程度上仍然是 未定义。最近，我们的初步研究表明，CCN 3作为TAAD的内源性抑制剂。 最近，我们的初步研究表明，由于CCN 3缺乏导致的内皮功能障碍 胸主动脉瘤和夹层（TAAD）动物。在马凡氏综合征的小鼠模型中， （Fbn 1 mgR/mgR），CCN 3缺乏的全面缺乏加重了马凡的胸主动脉瘤（TAA） 以主动脉根和升胸主动脉扩张增加为特征的小鼠， 血管夹层，因此增加了死亡率。类似的发现也被发现， 用血管紧张素II（Ang II）攻击动物。内皮限制性基因敲除小鼠（EC CCN 3-/-） 血管紧张素II输注后，主动脉根部和胸主动脉沿着扩张， 主动脉壁破坏的严重程度。从机制上讲，我们最初的批量RNAseq研究表明， CCN 3扰乱血管连接并引起参与血管连接的信号通路的异常激活。 炎症我们随后的体内和体外研究进一步支持了CCN 3的次要关键因素 缺乏（内皮屏障破坏、炎症、活性氧（ROS））导致内皮细胞 在TAAD的发展和进展中起着关键作用。这些观察提供了 本申请的中心假设的基础：CCN 3作为关键的生理调节剂， 维持对预防TAAD至关重要的内皮功能。本提案中的研究将 严格地处理这个假设。内皮细胞CCN 3在减轻TAAD中的作用将得到充分表征。 将研究CCN 3缺乏如何导致内皮功能障碍的机制基础。结果 这些研究将阐明CCN 3在控制内皮功能中的作用及其机制， 这是其促进内皮屏障完整性和限制炎症的能力的基础。

SUMMARY Aortic homeostasis is essential for vascular health. The vascular endothelium is a vital organ whose health is essential to normal vascular physiology; when dysregulated, it becomes a critical factor in the pathogenesis of a variety of vascular diseases. Growing evidence indicates that endothelial cells (ECs) play an underappreciated role in the development and progression of thoracic aortic aneurysm and dissection (TAAD). Most notably, compromised barrier integrity has been implicated as a precursor to the development of TAA. Work from our laboratory has led to the appreciation that a member of Cellular Communication Network (CCN) gene family, CCN3, serves as an important regulator of vascular health. However, the precise physiological role of CCN3 in vivo as well as the fundamental mechanisms responsible for CCN3’s action remain largely undefined. Recently, our preliminary studies suggest that CCN3 serves as an endogenous inhibitor of TAAD. Recently, our preliminary studies suggest that endothelial dysfunction due to CCN3 deficiency predisposes animals to thoracic aortic aneurysm and dissection (TAAD). In a mouse model of Marfan syndrome (Fbn1mgR/mgR), global deficiency of CCN3 deficiency exacerbates thoracic aortic aneurysm (TAA) in Marfan mice characterized by increased aortic root and ascending thoracic aortic dilation, elevated incidence of vessel dissection, and, as a consequence, enhanced mortality. Similar findings were obtained when challenging animals with angiotensin II (Ang II). Endothelial restricted knockout mice (EC CCN3-/-) subjected to Ang II infusion exhibited augmented aortic root and thoracic aortic dilation along with an elevated severity of aortic wall destruction. Mechanistically, our initial bulk RNAseq studies suggested that loss of CCN3 perturbs vascular junction and causes aberrant activation of signaling pathways involved in inflammation. Our subsequent in vivo and in vitro studies further support that key factors secondary to CCN3 deficiency (endothelial barrier disruption, inflammation, reactive oxygen species (ROS)) cause endothelial dysfunction and play a pivotal role in TAAD development and progression. These observations provide the foundation for the central hypotheses of this application: CCN3 serves as a critical physiological regulator for the maintenance of endothelial function essential for the prevention of TAAD. Studies in this proposal will rigorously address this hypothesis. The role of endothelial CCN3 in mitigating TAAD will be fully characterized. Mechanistic basis of how CCN3 deficiency leads to endothelial dysfunction will be investigated. The results of these studies will elucidate the role of CCN3 in controlling endothelial function and the mechanisms underlying its ability to promote endothelial barrier integrity and limit inflammation.