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.
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Abbreviations
- EB:
-
embryoid body
- EC:
-
endothelial cells
- HUVEC:
-
human umbilical vein cells
- iPSC:
-
induced pluripotent stem cells
- mESC:
-
mouse embryonic stem cells
- p73KO:
-
p73−/−
- TGF-β:
-
transforming growth factor-β
- VEGF:
-
vascular endothelial growth factor
- WT:
-
wild type
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Acknowledgements
This work was supported by Grants SAF2012-36143 from Spanish Ministerio de Economía y Competitividad and cofinanced by FEDER funds (to MCM), and Grant LE015A10-2 from the Junta de Castilla y Leon (to MCM). RF-A was holder of a predoctoral scholarship from the Spanish Ministry of Science and Education (AP2007-02022). MM-L is a holder of a predoctoral scholarship from Junta de Castilla y Leon (PIRTU 2010). Work in the LCW lab was supported by Grants from the Swedish Cancer Foundation and Swedish Science Council. We thank the Instituto Biomar SA (Leon, Spain) for kindly supplying HUVEC and B16-F10 cells. We also thank the Pathology Deparment at the Complejo Hospitalario de Leon (Leon, Spain) for technical help and assistance in tumor analysis.
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Fernandez-Alonso, R., Martin-Lopez, M., Gonzalez-Cano, L. et al. p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling. Cell Death Differ 22, 1287–1299 (2015). https://doi.org/10.1038/cdd.2014.214
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DOI: https://doi.org/10.1038/cdd.2014.214
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