GSE129564
Control of aortic root formation by SOX17 links aortic valve defects to coronary artery anomalies
Located at the junction of left ventricle and ascending aorta, aortic root is a central cardiovascular structure consisting of aortic valve and coronary ostium that are essential for systemic and coronary circulation, respectively. Malformations of aortic valve and coronary ostium are common birth defects and may occur together in human patients, leading to complex complications including aortic valve stenosis, myocardial ischemia, heart failure and sudden cardiac death. Despite of their physiological and clinical significances, the developmental and molecular mechanisms by which coordinate the formation of aortic valve and coronary ostium remain poorly understood. Here we report that SOX17 (SRY-box 17) is an essential transcription factor required for the maturation of aortic root, as well as the patterning of aortic valve and coronary ostium. We show in mouse that deletion of Sox17 in the aortic root endothelium results in defective aortic valve with underdeveloped non-coronary leaflet (NCL) or bicuspid aortic valve (BAV) without NCL. The valve defects are accompanied by misplaced left coronary ostium that reduces coronary blood flow, leading to myocardial hypoxia and death of embryos. Mechanistically, deletion of Sox17 decreases the expression of Pdgfb (Platelet derived growth factor, B polypeptide) in the aortic root endothelium and the PDGF growth signaling in the NCL mesenchyme and aortic root smooth muscle, both of which are derived from the second heart field (SHF) cardiomyocyte precursors. Furthermore, the deletion upregulates the expression of Ctgf (Connective tissue growth factor) and the extracellular matrix (ECM) genes, whereas downregulates the vascular smooth muscle genes, in the forming aortic root. Together, these findings support a developmental disease mechanism in which delayed growth and maturation of aortic root, due to lack of SOX17-PDGF/CTGF signaling, contributes to BAV and CAAs, two common congenital cardiovascular defects. Overall design: we performed RNA-seq analysis of E12.5 wild type (WT) and Sox17eKO outflow tract (OFT) to identify Sox17 targets. Each group included two biological replicates, by pooling from 10 hearts' OFT for each replicate