TY - JOUR T1 - Desert Hedgehog-driven endothelium integrity is enhanced by Gas1 but negatively regulated by Cdon JF - bioRxiv DO - 10.1101/2020.04.20.050542 SP - 2020.04.20.050542 AU - Candice Chapouly AU - Pierre-Louis Hollier AU - Sarah Guimbal AU - Lauriane Cornuault AU - Alain-Pierre Gadeau AU - Marie-Ange Renault Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/04/20/2020.04.20.050542.abstract N2 - Evidences accumulated within the past decades, identified Hedgehog (Hh) signaling as a new regulator of micro-vessel integrity. More specifically, we recently identified Desert Hedgehog (Dhh) as a downstream effector of Klf2 in endothelial cells (ECs).Objective The purpose of this study is to investigate whether Hh co-receptors Gas1 and Cdon may be used as therapeutic targets to modulate Dhh signaling in ECs.Methods and results We demonstrated that both Gas1 and Cdon are expressed in adult ECs and relied on either siRNAs or EC specific conditional KO mice to investigate their role. We found that Gas1 deficiency mainly photocopies Dhh deficiency especially by inducing VCAM-1 and ICAM-1 overexpression while Cdon deficiency has opposite effects by promoting endothelial junction integrity. At a molecular level, Cdon prevents Dhh binding to Ptch1 and thus acts a decoy receptor for Dhh, while Gas1 promotes Dhh binding to Smo and as a result potentiates Dhh effects. Since Cdon is overexpressed in ECs treated by inflammatory cytokines including TNFα and Il1β, we then tested whether Cdon inhibition would promote endothelium integrity in acute inflammatory conditions and found that both fibrinogen and IgG extravasation were decreased in association with an increased Cdh5 expression in the brain cortex of EC specific Cdon KO mice administered locally with Il1β.Conclusion Altogether these results demonstrate that Gas1 is a positive regulator of Dhh in ECs while Cdon is a negative regulator. Interestingly Cdon blocking molecules may then be used to promote endothelium integrity at least in inflammatory conditions.Competing Interest StatementThe authors have declared no competing interest. ER -