PT  - JOURNAL ARTICLE
AU  - Santiago Ruiz
AU  - Pallavi Chandakkar
AU  - Haitian Zhao
AU  - Julien Papoin
AU  - Prodyot K. Chatterjee
AU  - Erica Christen
AU  - Christine N. Metz
AU  - Lionel Blanc
AU  - Fabien Campagne
AU  - Philippe Marambaud
TI  - Tacrolimus rescues endothelial ALK1 loss-of-function signaling and improves HHT vascular pathology
AID  - 10.1101/137737
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 137737
4099  - http://biorxiv.org/content/early/2017/05/13/137737.short
4100  - http://biorxiv.org/content/early/2017/05/13/137737.full
AB  - Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder arising from endothelial cell (EC) proliferation and hypervascularization, for which no cure exists. Because HHT is caused by loss-of-function mutations in BMP9-ALK1-Smad1/5/8 signaling, interventions aimed at activating this pathway are of therapeutic value. By screening FDA-approved drug libraries, we identified tacrolimus (FK-506) as a potent activator of Smad1/5/8 in BMP9-challenged reporter cells. In primary ECs, tacrolimus activated Smad1/5/8 to oppose the pro-angiogenic gene expression signature associated with ALK1 loss-of-function, by notably reducing Dll4 expression. In these cells, tacrolimus also inhibited Akt and p38 stimulation by VEGF. In the BMP9/10-immunodepleted postnatal retina—a mouse model of HHT vascular pathology—tacrolimus activated endothelial Smad1/5/8 and prevented the Dll4 overexpression and hypervascularization associated with this model. Finally, tacrolimus stimulated Smad1/5/8 in cells transfected with BMP9-unresponsive ALK1 HHT mutants and in HHT patient blood outgrowth ECs. We propose that tacrolimus repurposing has therapeutic potential in HHT.