title: Extracardiac septum transversum/proepicardial endothelial cells pattern embryonic coronary arterio-venous connections.
abstract: 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(Cre)) and previously undescribed (G2-Gata4(Cre)) 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 of G2-Gata4(Cre) mice and in the endothelium of Tie2(Cre) 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.
authors.affiliation: Department of Animal Biology, Faculty of Sciences, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29071 Málaga, Spain; Group of Cardiovascular Genetics, Department of Vertebrate Genomics and Cardiovascular Genetics, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin 13125, Germany; Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany;
authors.forename: Elena
authors.initials: E
authors.lastname: Cano
authors.affiliation: Department of Animal Biology, Faculty of Sciences, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29071 Málaga, Spain; Andalusian Center for Nanomedicine and Biotechnology (BIONAND), 29590 Málaga, Spain;
authors.forename: Rita
authors.identifier: http://orcid.org/0000-0002-9686-473X
authors.initials: R
authors.lastname: Carmona
authors.affiliation: Department of Animal Biology, Faculty of Sciences, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29071 Málaga, Spain; Department of Anatomy, Embryology and Physiology, Academic Medical Center-University of Amsterdam, AZ1105 Amsterdam, The Netherlands;
authors.forename: Adrián
authors.initials: A
authors.lastname: Ruiz-Villalba
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa, 41092 Sevilla, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 41092 Sevilla, Spain;
authors.forename: Anabel
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Medical Research Council Human Genetics Unit, Western General Hospital, EH4 2XU, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital, EH4 2XU, Edinburgh, United Kingdom;
authors.forename: You-Ying
authors.initials: YY
authors.lastname: Chau
authors.affiliation: Institut de Biologie Valrose, Université Nice Sophia, CNRS, INSERM, 06108 Nice, France.
authors.forename: Kay D
authors.initials: KD
authors.lastname: Wagner
authors.affiliation: Institut de Biologie Valrose, Université Nice Sophia, CNRS, INSERM, 06108 Nice, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wagner
authors.affiliation: Medical Research Council Human Genetics Unit, Western General Hospital, EH4 2XU, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital, EH4 2XU, Edinburgh, United Kingdom;
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.affiliation: Department of Animal Biology, Faculty of Sciences, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29071 Málaga, Spain; Andalusian Center for Nanomedicine and Biotechnology (BIONAND), 29590 Málaga, Spain;
authors.forename: Ramón
authors.initials: R
authors.lastname: Muñoz-Chápuli
authors.affiliation: Department of Animal Biology, Faculty of Sciences, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29071 Málaga, Spain; Andalusian Center for Nanomedicine and Biotechnology (BIONAND), 29590 Málaga, Spain; jmperezp@uma.es.
authors.forename: José M
authors.initials: JM
authors.lastname: Pérez-Pomares
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage; D003331:Coronary Vessels / Q000166:cytology / Q000196:embryology*; D004622:Embryo, Mammalian / Q000166:cytology*; D047108:Embryonic Development; D042783:Endothelial Cells / Q000166:cytology*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D050991:GATA4 Transcription Factor / Q000378:metabolism; D017353:Gene Deletion; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006346:Heart Septum / Q000166:cytology*; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010496:Pericardium / Q000166:cytology*; D010641:Phenotype; D025721:WT1 Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D050991:GATA4 Transcription Factor; D025721:WT1 Proteins; D049452:Green Fluorescent Proteins; C045073:Cre recombinase; D019426:Integrases
keywords: Gata4; Wt1; coronary endothelium; proepicardium; septum transversum