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oai:repisalud.isciii.es:20.500.12105/89292024-09-27T08:44:22Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605col_20.500.12105_19607

00925njm 22002777a 4500 dc Travisano, Stanislao Igor author Oliveira, Vera Lucia author Prados, Belen author Grego-Bessa, Joaquim author Piñeiro-Sabarís, Rebeca author Bou, Vanesa author Gomez, Manuel J author Sanchez-Cabo, Fatima author MacGrogan, Donal author de la Pompa, Jose Luis author 2019-12 Coronaries are essential for myocardial growth and heart function. Notch is crucial for mouse embryonic angiogenesis, but its role in coronary development remains uncertain. We show Jag1, Dll4 and activated Notch1 receptor expression in sinus venosus (SV) endocardium. Endocardial Jag1 removal blocks SV capillary sprouting, while Dll4 inactivation stimulates excessive capillary growth, suggesting that ligand antagonism regulates coronary primary plexus formation. Later endothelial ligand removal, or forced expression of Dll4 or the glycosyltransferase Mfng, blocks coronary plexus remodeling, arterial differentiation, and perivascular cell maturation. Endocardial deletion of Efnb2 phenocopies the coronary arterial defects of Notch mutants. Angiogenic rescue experiments in ventricular explants, or in primary human endothelial cells, indicate that EphrinB2 is a critical effector of antagonistic Dll4 and Jag1 functions in arterial morphogenesis. Thus, coronary arterial precursors are specified in the SV prior to primary coronary plexus formation and subsequent arterial differentiation depends on a Dll4-Jag1-EphrinB2 signaling cascade. Elife. 2019; 8:e49977 2050-084X http://hdl.handle.net/20.500.12105/8929 31789590 10.7554/eLife.49977 2050-084X eLife EphrinB2 NOTCH Coronaries Developmental biology Erial-venous differentiation Mouse Sinus venosus Vessel morphogenesis Coronary arterial development is regulated by a Dll4-Jag1-EphrinB2 signaling cascade