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.

The p53 family and the hypoxia-inducible factors (HIFs): determinants of cancer progression

“…Consistently, a third group reported that constitutive p73 deficiency (both TAp73 and DNp73) impairs vascular development in mouse retina. In particular, DNp73 [the predominantly expressed isoform in endothelial cells (EC)], but not TAp73 (poorly expressed), promotes in vitro EC tube formation and migration as well as in vivo vascularization of tumor xenografts [31]. Overall, independent groups have consistently reported opposite roles for TAp73 and DNp73, respectively, in repressing and promoting angiogenesis.…”

Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases

“…p53, TAp73 and TAp63 have been described to counteract HIF-1 activity affecting its stability though direct or indirect mechanisms Amelio and Melino, 2012;Fernandez-Alonso et al, 2015;Montagner et al, 2012;Ravi et al, 2000). These signalling generate oxygen-independent regulation of HIF-1 that impact on the tumorigenic potential of cancer cells, affecting angiogenesis, metabolism and metastasis .…”

Evaluation of promoter hypomethylation and expression ofp73as a diagnostic and prognostic biomarker in Wilms’ tumour

“…Moreover, expression of p73 was increased with higher degrees of tumour malignancy, supporting the theory that excessive levels contribute to tumour progression, similar to our previous observations 42. An earlier study using a melanoma cell line reported that overexpression of p73 enhances tumour progression due to its pro-angiogenic capacity via regulation of pro-angiogenic factors, such as transforming growth factor-β and vascular endothelial growth factors 62. Sablina et al observed that increased p73 transcriptional activity is accompanied by human lung carcinoma cell migration 63.…”