title: p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling.
abstract: Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-β and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.
authors.affiliation: Instituto de Biomedicina (IBIOMED), Departamento de Biologia Molecular, University of Leon, Campus de Vegazana, 24071 Leon, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Fernandez-Alonso
authors.affiliation: Instituto de Biomedicina (IBIOMED), Departamento de Biologia Molecular, University of Leon, Campus de Vegazana, 24071 Leon, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Martin-Lopez
authors.affiliation: Instituto de Biomedicina (IBIOMED), Departamento de Biologia Molecular, University of Leon, Campus de Vegazana, 24071 Leon, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Gonzalez-Cano
authors.affiliation: Instituto de Biomedicina (IBIOMED), Departamento de Biologia Molecular, University of Leon, Campus de Vegazana, 24071 Leon, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Garcia
authors.affiliation: Instituto de Biomedicina (IBIOMED), Departamento de Biologia Molecular, University of Leon, Campus de Vegazana, 24071 Leon, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Castrillo
authors.affiliation: 1] Instituto de Biomedicina (IBIOMED), Departamento de Biologia Molecular, University of Leon, Campus de Vegazana, 24071 Leon, Spain [2] Departamento de Medicina, Cirugia y Anatomia Veterinaria, University of Leon, Campus de Vegazana, 24071 Leon, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Diez-Prieto
authors.affiliation: 1] Instituto de Biomedicina (IBIOMED), Departamento de Biologia Molecular, University of Leon, Campus de Vegazana, 24071 Leon, Spain [2] Complejo Hospitalario de Leon, Altos de Nava s/n, 24071 Leon, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Fernandez-Corona
authors.affiliation: 1] Instituto de Biomedicina (IBIOMED), Departamento de Biologia Molecular, University of Leon, Campus de Vegazana, 24071 Leon, Spain [2] Complejo Hospitalario de Leon, Altos de Nava s/n, 24071 Leon, Spain.
authors.forename: M E
authors.initials: ME
authors.lastname: Lorenzo-Marcos
authors.affiliation: Rudbeck Laboratory and Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarksjöldsv 20, 751 85 Uppsala, Sweden.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Rudbeck Laboratory and Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarksjöldsv 20, 751 85 Uppsala, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Claesson-Welsh
authors.affiliation: Instituto de Desarrollo Ganadero, University of Leon, Campus de Vegazana, 24071 Leon, Spain.
authors.forename: M M
authors.initials: MM
authors.lastname: Marques
authors.affiliation: Instituto de Biomedicina (IBIOMED), Departamento de Biologia Molecular, University of Leon, Campus de Vegazana, 24071 Leon, Spain.
authors.forename: M C
authors.initials: MC
authors.lastname: Marin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; D016212:Transforming Growth Factor beta; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A