Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
School of Medical Imaging, Tianjin Medical University, Tianjin, China.
Nat Commun. 2022 Jul 13;13(1):4065. doi: 10.1038/s41467-022-31815-1.
Developmental etiologies causing complex congenital aortic root abnormalities are unknown. Here we show that deletion of Sox17 in aortic root endothelium in mice causes underdeveloped aortic root leading to a bicuspid aortic valve due to the absence of non-coronary leaflet and mispositioned left coronary ostium. The respective defects are associated with reduced proliferation of non-coronary leaflet mesenchyme and aortic root smooth muscle derived from the second heart field cardiomyocytes. Mechanistically, SOX17 occupies a Pdgfb transcriptional enhancer to promote its transcription and Sox17 deletion inhibits the endothelial Pdgfb transcription and PDGFB growth signaling to the non-coronary leaflet mesenchyme. Restoration of PDGFB in aortic root endothelium rescues the non-coronary leaflet and left coronary ostium defects in Sox17 nulls. These data support a SOX17-PDGFB axis underlying aortic root development that is critical for aortic valve and coronary ostium patterning, thereby informing a potential shared disease mechanism for concurrent anomalous aortic valve and coronary arteries.
导致复杂先天性主动脉根部异常的发育病因尚不清楚。在这里，我们显示 Sox17 在小鼠主动脉根部内皮中的缺失导致主动脉根部发育不良，导致二叶式主动脉瓣，原因是无冠状动脉瓣和左冠状动脉口错位。各自的缺陷与非冠状动脉瓣间充质和源自第二心区心肌细胞的主动脉根部平滑肌的增殖减少有关。在机制上，SOX17 占据 PDGFB 转录增强子以促进其转录，而 Sox17 缺失抑制内皮 PDGFB 转录和 PDGFB 对非冠状动脉瓣间充质的生长信号。主动脉根部内皮中 PDGFB 的恢复可挽救 Sox17 缺失小鼠的非冠状动脉瓣和左冠状动脉口缺陷。这些数据支持主动脉根部发育的 SOX17-PDGFB 轴，这对于主动脉瓣和冠状动脉口模式形成至关重要，从而为同时存在的异常主动脉瓣和冠状动脉提供了潜在的共同疾病机制。
