Marco Morini

The mechanistic foundation of vascular stability is still largely unknown. A gene profile analysis reveals that the expression of the endothelial specific, adherens junction protein VE-cadherin upregulates a set of genes important in vascular stability that includes claudin-5, VE-PTP and von Willebrand factor. Mechanistic studies indicate that VE-cadherin exerts this effect by inhibiting the nuclear translocation of FoxO1 and b-catenin that, in turn, anchor the Polycomb multiprotein repressive complex (PRC2) to specific promoters. VE-cadherin also sequesters a core subunit of PRC2 (Ezh2) at the cell membrane thus preventing its nuclear translocation. Dismantling of VE-cadherin clusters during pathological angiogenesis in human ovarian carcinomas is accompanied by increase in EZH2 and down-regulation of claudin-5. These data introduce the novel concept of an inhibitory role of Polycomb proteins in EC differentiation and vascular stability and open novel therapeutic opportunities to induce vascular normalization through inhibition of the Polycomb-mediated repression system.