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Endothelial to mesenchymal transition (EndMT) is a leading cause of fibrosis and disease, however its mechanism has yet to be elucidated. The endothelium possesses a profound regenerative capacity to adapt and reorganize that is attributed to a population of vessel-resident endovascular progenitors (EVP) governing an endothelial hierarchy. Here, using fate analysis, we show that two transcription factors SOX9 and RBPJ specifically affect the murine EVP numbers and regulate lineage specification. Conditional knock-out of  Sox9  from the vasculature ( Sox9   fl/fl   /Cdh5-Cre   ER    RosaYFP ) depletes EVP while enhancing  Rbpj  expression and canonical Notch signalling. Additionally, skin wound analysis from  Sox9  conditional knock-out mice demonstrates a significant reduction in pathological EndMT resulting in reduced scar area. The converse is observed with  Rbpj  conditionally knocked-out from the murine vasculature ( Rbpj   fl/fl   /Cdh5-CreER RosaYFP ) or inhibition of Notch signaling in human endothelial colony forming cells, resulting in enhanced  Sox9  and EndMT related gene ( Snail, Slug, Twist1, Twist2, TGF-β ) expression. Similarly, increased endothelial hedgehog signaling ( Ptch1   fl/fl   /Cdh5-CreER RosaYFP ), that upregulates the expression of  Sox9  in cells undergoing pathological EndMT, also results in excess fibrosis. Endothelial cells transitioning to a mesenchymal fate express increased  Sox9 , reduced  Rbpj  and enhanced EndMT. Importantly, using topical administration of siRNA against  Sox9  on skin wounds can substantially reduce scar area by blocking pathological EndMT. Overall, here we report distinct fates of EVPs according to the relative expression of  Rbpj  or Notch signalling and  Sox9 , highlighting their potential plasticity and opening exciting avenues for more effective therapies in fibrotic diseases.

Sox9 and Rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors