Extracardiac septum transversum/proepicardial endothelial cells pattern embryonic coronary arterio-venous connections

Cano, Elena et al.Recent reports suggest that mammalian embryonic coronary endothelium (CoE) originates from the sinus venosus and ventricular endocardium. However, the contribution of extracardiac cells to CoE is thought to be minor and nonsignificant for coronary formation. Using classic (Wt1) and previously undescribed (G2-Gata4) transgenic mouse models for the study of coronary vascular development, we show that extracardiac septum transversum/proepicardium (ST/PE)-derived endothelial cells are required for the formation of ventricular coronary arterio-venous vascular connections. Our results indicate that at least 20% of embryonic coronary arterial and capillary endothelial cells derive from the ST/PE compartment. Moreover, we show that conditional deletion of the ST/PE lineage-specific Wilms' tumor suppressor gene (Wt1) in the ST/PE ofG2-Gata4 mice and in the endothelium of Tie2 mice disrupts embryonic coronary transmural patterning, leading to embryonic death. Taken together, our results demonstrate that ST/PE-derived endothelial cells contribute significantly to and are required for proper coronary vascular morphogenesis.This research was supported by Ministry of Economy and Competitiveness Grants BFU2012-35799 and ISCIII-RD12/0019-0022 (to J.M.P.-P.) and BFU2011-25304 (to R.M.-C.); European Commission Seventh Framework Program-Marie Curie-Innovative Training Network Action PITNGA-2011-289600 (to J.M.P.-P.); Junta de Andalucía CTS-7564 (to R.M.-C. and J.M.P.-P.); Instituto de Salud Carlos III-Fondos FEDER Grant PI14/00814 (to A.R.); the French Government National Research Agency through the Laboratory of Excellence SIGNALIFE program (reference ANR-11-LABX-0028-01) (K.D.W.); the Association pour la Recherche sur le Cancer Grant R13026AA-ARC-WAGNER (to K.D.W.); and Fondation de France Grant FDF-U1081-WAGNER (to K.D.W.).Peer Reviewe