Proposed model for E2-mediated activation of VEGF-A-Dll4-Notch1 signalling and consequences on sprouting angiogenesis in HUVECs.

<p>According to a widely accepted model <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071440#pone.0071440-Sainson1" target="_blank">[5]</a> Vascular Endothelial Growth Factor A (VEGF-A), by binding to VEGF Receptor-2 (VEGF-R2), promotes sprouting on endothelial cells and induces expression of Dll4 which, by activating Notch1 in adjacent cells leads to reduction of VEGF-R2 and inhibition of sprouting (A). E2 treatment enhances VEGF-A-mediated increase of the active form of Notch1 (N1IC), effect antagonized by the estrogen receptor antagonist ICI 182.780. In the presence of active Notch1 signalling, a further increase of N1IC induced by E2 does not affect sprouting (B). Notch1 inhibition by treatment with DAPT causes increased sprouting (C). Co-treatment with E2 counteracts DAPT-induced increase in vascular sprouting through still undetermined mechanisms (D).