Authors

Fernandez-Alonso R.1*, Martin-Lopez, M.1*, Gonzalez-Cano L.1,+, Garcia- S.1, Castrillo F1., Diez-Prieto I.1,2, Fernandez-Corona A.1, 3, Lorenzo-Marcos ME.1,3, Li X.4, Claesson-Welsh L.4, Marques, M.M.5 & Marin, M.C.1** *Equal Contribution **Corresponding author: Dr. M.C. Marin, IBIOMED, Universidad de Leon, Campus de Vegazana, 24071 Leon, Spain. Tel: + 34-987-291793; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. | web: http://institutobiomedicina.unileon.es/ibmx_grupo10Eng.htm

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.

Description

En este artículo, publicado recientemente en Cell Death and Differentiation, estudiamos la función del gen TP73 en los procesos de vasculogénesis y angiogénesis tanto in vivo como in vitro. Para ello, utilizamos retinas de ratones neonatos y modelos de diferenciación endotelial en 2D y 3D a partir de células troncales embrionarias y células iPS. Demostramos que p73 regula estos procesos mediante la modulación de las vías de VEGF y TGFβ. Observamos que una de las isoformas de p73, DNp73, regula la migración de las células endoteliales e incrementa su potencial angiogénico. Consecuentemente, la expresión de esta isoforma se incrementa en el contexto del microambiente tumoral, lo cual contribuye a aumentar el potencial angiogénico del tumor. Nuestros datos demuestran, por primera vez, que la regulación diferencial del gen TP73 es un factor fundamental tanto en procesos fisiológicos de vasculogénesis y angiogénesis, como durante la angiogénesis y progresión tumoral.

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REFERENCIA DEL GRUPO INVESTIGADOR

Nuestro grupo, dirigido por la Dra. Carmen Marín y la Dra. Margarita Marqués Martínez, constituye el grupo de Diferenciación Celular y Diseño de Modelos Celulares integrado en el Instituto de Biomedicina (IBIOMED) de León. (http://institutobiomedicina.unileon.es/ibmx_grupo10.htm). Nuestra actividad investigadora se centra en identificar las interacciones funcionales de los genes que componen la familia de p53, en particular, p73 y p53, en la biología de las células troncales, en la organización de los nichos neurogénicos, la reprogramación celular y en los procesos de vasculogénesis y angiogénesis. Actualmente, Marta Martín López está finalizando su Tesis Doctoral sobre la función de p73 durante el proceso de reprogramación celular, y la Dra. Fernandez-Alonso es investigadora postdoctoral en el College of Life Sciences de la Universidad de Dundee.

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