Scientific Research Center, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Clin Sci (Lond). 2021 Mar 26;135(6):829-846. doi: 10.1042/CS20201496.
The endothelial-to-mesenchymal transition (EndMT) is a critical process that occurs during the development of the outflow tract (OFT). Malformations of the OFT can lead to the occurrence of conotruncal defect (CTD). SOX7 duplication has been reported in patients with congenital CTD, but its specific role in OFT development remains poorly understood. To decipher this, histological analysis showed that SRY-related HMG-box 7 (SOX7) was regionally expressed in the endocardial endothelial cells and in the mesenchymal cells of the OFT, where EndMT occurs. Experiments, using in vitro collagen gel culture system, revealed that SOX7 was a negative regulator of EndMT that inhibited endocardial cell (EC) migration and resulted in decreased number of mesenchymal cells. Forced expression of SOX7 in endothelial cells blocked further migration and improved the expression of the adhesion protein vascular endothelial (VE)-cadherin (VE-cadherin). Moreover, a VE-cadherin knockdown could partly reverse the SOX7-mediated repression of cell migration. Luciferase and electrophoretic mobility shift assay (EMSA) demonstrated that SOX7 up-regulated VE-cadherin by directly binding to the gene's promoter in endothelial cells. The coding exons and splicing regions of the SOX7 gene were also scanned in the 536 sporadic CTD patients and in 300 unaffected controls, which revealed four heterozygous SOX7 mutations. Luciferase assays revealed that two SOX7 variants weakened the transactivation of the VE-cadherin promoter. In conclusion, SOX7 inhibited EndMT during OFT development by directly up-regulating the endothelial-specific adhesion molecule VE-cadherin. SOX7 mutations can lead to impaired EndMT by regulating VE-cadherin, which may give rise to the molecular mechanisms associated with SOX7 in CTD pathogenesis.
内皮到间充质转化（EndMT）是流出道（OFT）发育过程中的一个关键过程。OFT 的畸形可导致圆锥动脉干畸形（CTD）的发生。SOX7 重复已在先天性 CTD 患者中报道，但它在 OFT 发育中的具体作用仍知之甚少。为了解密这一点，组织学分析表明，性别决定区 Y 相关高迁移率族框 7（SOX7）在心内膜内皮细胞和 OFT 的间充质细胞中呈区域性表达，EndMT 在此发生。使用体外胶原凝胶培养系统的实验表明，SOX7 是 EndMT 的负调节因子，可抑制心内膜细胞（EC）迁移，并导致间充质细胞数量减少。SOX7 在血管内皮细胞中的强制表达阻止了进一步的迁移，并改善了黏附蛋白血管内皮（VE）-钙黏蛋白（VE-cadherin）的表达。此外，VE-cadherin 的敲低部分逆转了 SOX7 介导的细胞迁移抑制。荧光素酶和电泳迁移率变动分析（EMSA）表明，SOX7 通过直接结合内皮细胞中基因的启动子而上调 VE-cadherin 的表达。还在 536 例散发性 CTD 患者和 300 例无影响对照中扫描了 SOX7 基因的编码外显子和剪接区，发现了四个杂合 SOX7 突变。荧光素酶检测表明，两种 SOX7 变体削弱了 VE-cadherin 启动子的转录激活。总之，SOX7 通过直接上调内皮特异性黏附分子 VE-cadherin 来抑制 OFT 发育过程中的 EndMT。SOX7 突变通过调节 VE-cadherin 导致 EndMT 受损，这可能为 CTD 发病机制中与 SOX7 相关的分子机制提供了线索。
