Transcriptional regulation during development of the ductus arteriosus.
Transcriptional regulation during development of the ductus arteriosus.
复制标题
DOI：
10.1161/circresaha.108.180661
复制
发表时间：
2008-08-15
影响因子：
20.1
通讯作者：
Srivastava D
中科院分区：
文献类型：
--
作者：
Ivey KN;Sutcliffe D;Richardson J;Clyman RI;Garcia JA;Srivastava D
动脉导管是一种特殊的血管，含有高度分化和收缩的血管平滑肌，主要来源于神经嵴细胞，对胎儿生命至关重要，但通常在出生后关闭。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通畅，这是第三种最常见的先天性心脏病。我们发现Tfap 2 β，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唯一表达。内皮素-1和低氧诱导的转录因子HIF 2 α在胚胎13.5天的导管平滑肌中也高度富集，并且依赖于Tfap 2 β在该区域的表达。HIF 2 α通过破坏蛋白质-DNA相互作用对Tfap 2 β诱导的转录起负调控作用，提示存在负反馈环调控Tfap 2 β活性。我们的数据表明，Tfap 2 β、Et-1和Hif 2 α在导管平滑肌发育期间在转录网络中起作用，并且该途径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。
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 post-natal closure, can result in persistent patency of the ductus arteriosus, the third most common congenital heart defect. We found that Tfap2β, 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, Hif2α were also highly enriched in ductal smooth muscle at embryonic day 13.5 and were dependent on Tfap2β for their expression in this domain. Hif2α functioned as a negative regulator of Tfap2β–induced transcription by disrupting protein–DNA interactions, suggesting a negative feedback loop regulating Tfap2β activity. Our data indicate that Tfap2β, Et-1, and Hif2α 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.