Active repression of Sox9 by Jag1 is required for silencing the default chondrogenic fate of the vascular smooth muscle wall [set 1]. Mus musculus

Acquisition and maintenance of vascular smooth muscle fate is essential for the morphogenesis and function of the circulatory system. Loss of contractile properties or changes in the identity of vascular smooth muscle cells (vSMC) can result in structural alterations associated with aneurysms and vascular wall calcifications. Here we report that maturation of sclerotome-derived vSMC is dependent on a transcriptional switch between mouse embryonic days 13 and 14.5. At this time point, Jag1-mediated repression of sclerotome transcription factors Pax1, scleraxis and Sox9 is necessary to fully enable vSMC maturation. Specifically, Notch signaling in vSMC antagonizes sclerotome and cartilage transcription factors, and promotes upregulation of contractile genes. In the absence of Jag1, vSMC acquire a chondrocytic transcriptional repertoire that can lead to ossification of the vascular wall. Importantly, our findings suggest that sustained Notch signaling is essential throughout vSMC life to maintain contractile function, prevent vSMC reprogramming and promote vascular wall integrity. Overall design: mRNA profile of vascular Smooth Muscle Cells, isolated from the descending aorta of Immorto mouse, treated or not with gamma-secretase inhibitor was generated by deep sequencing, in triplicate.

血管平滑肌细胞（vascular smooth muscle cell, vSMC）命运的获取与维持，对于循环系统的形态发生与功能行使至关重要。血管平滑肌细胞收缩特性的丧失或细胞身份的改变，可引发与动脉瘤及血管壁钙化相关的结构病变。本研究报道，生骨节来源的血管平滑肌细胞的成熟，依赖于小鼠胚胎第13天至14.5天之间发生的转录转换。在该时间节点，Jag1介导的对生骨节转录因子Pax1、Scleraxis及Sox9的抑制作用，是完全实现血管平滑肌细胞成熟的必要前提。具体而言，血管平滑肌细胞中的Notch信号通路可拮抗生骨节与软骨转录因子，并促进收缩相关基因的表达上调。在Jag1缺失的条件下，血管平滑肌细胞会获得软骨细胞样的转录谱，进而可能导致血管壁骨化。值得关注的是，本研究结果提示，在血管平滑肌细胞的整个生命周期中，持续的Notch信号通路激活对于维持其收缩功能、阻止细胞重编程以及保障血管壁完整性均必不可少。实验设计：本研究通过深度测序技术，对经γ-分泌酶抑制剂处理或未处理的Immorto小鼠降主动脉分离得到的血管平滑肌细胞的mRNA表达谱进行检测，所有样本均设置三次生物学重复。