Seminar

PTEN restricts endothelial cell proliferation to control vessel density in Angiogenesis

Mariona Graupera, Phd

PTEN is a tumor suppressor gene, which is among the most frequently mutated in cancer. PTEN opposes the phosphoinositide-3-kinase (PI3K)/Akt pathway through dephosphorylation of phosphoinositide-3,4,5-triphosphate (PIP3). Loss of PTEN function leads to activation of the PI3K pathway, which stimulates cell growth and survival. Remarkably, emerging data show that PTEN also has PI3K independent functions. Previous studies have shown the relevance of PTEN in vascular development. However, progress in the understanding of how PTEN regulates angiogenesis has been hampered by the embryonic lethality that exhibit both the constitutive and endothelial-specific PTEN mutant mice. Hence, in order to circumvent this problem, we selectively inactivated PTEN in adult vasculature, by breeding PTEN-flox mice to tamoxifen-inducible Pdgfb-iCreER transgenic mouse line in which Cre is only active in endothelial cells after tamoxifen administration. Preliminary data obtained in postnatal retinas of PTEN-flox/Pdgfb-iCreER mice illustrates that deletion of PTEN leads to dramatic branching defects and aberrant vascular patterning of the nascent plexus. Here, we will discuss which endothelial functions are being affected upon PTEN deletion and how they are contributing to the phenotype observed. An important conclusion from our data is that the phenotype obtained upon PTEN deletion cannot be only explained by up-regulation of PIP3 levels, suggesting that PTEN also exerts lipid phosphatase independent functions in angiogenesis.