Ivey Kathryn N, Sutcliffe David, Richardson James, Clyman Ronald I, Garcia Joseph A, Srivastava Deepak
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA.
Circ Res. 2008 Aug 15;103(4):388-95. doi: 10.1161/CIRCRESAHA.108.180661. Epub 2008 Jul 17.
The ductus arteriosus is a specialized blood vessel containing highly differentiated and contractile vascular smooth muscle, derived largely from neural crest cells, that is essential for fetal life but typically closes after birth. Impaired development of the ductus arteriosus or disruption of signaling pathways that initiate postnatal closure can result in persistent patency of the ductus arteriosus, the third most common congenital heart defect. We found that Tfap2beta, a transcription factor associated with patent ductus arteriosus in humans, was uniquely expressed in mouse ductal smooth muscle. Endothelin-1 and the hypoxia-induced transcription factor, Hif2alpha were also highly enriched in ductal smooth muscle at embryonic day 13.5 and were dependent on Tfap2beta for their expression in this domain. Hif2alpha functioned as a negative regulator of Tfap2beta-induced transcription by disrupting protein-DNA interactions, suggesting a negative feedback loop regulating Tfap2beta activity. Our data indicate that Tfap2beta, Et-1, and Hif2alpha act in a transcriptional network during ductal smooth muscle development and that disruption of this pathway may contribute to patent ductus arteriosus by affecting the development of smooth muscle within the ductus arteriosus.
动脉导管是一种特殊的血管，含有高度分化且可收缩的血管平滑肌，这种平滑肌主要源自神经嵴细胞，它对胎儿生命至关重要，但通常在出生后闭合。动脉导管发育受损或启动出生后闭合的信号通路中断可导致动脉导管持续开放，这是第三常见的先天性心脏缺陷。我们发现，Tfap2beta是一种与人类动脉导管未闭相关的转录因子，在小鼠导管平滑肌中独特表达。内皮素-1和缺氧诱导转录因子Hif2alpha在胚胎第13.5天时在导管平滑肌中也高度富集，且它们在该区域的表达依赖于Tfap2beta。Hif2alpha通过破坏蛋白质-DNA相互作用发挥Tfap2beta诱导转录的负调节作用，提示存在调节Tfap2beta活性的负反馈回路。我们的数据表明，Tfap2beta、Et-1和Hif2alpha在导管平滑肌发育过程中作用于一个转录网络，并且该通路的破坏可能通过影响动脉导管内平滑肌的发育而导致动脉导管未闭。
