RT Journal Article
SR Electronic
T1 Tacrolimus rescues endothelial ALK1 loss-of-function signaling and improves HHT vascular pathology
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 137737
DO 10.1101/137737
A1 Ruiz, Santiago
A1 Chandakkar, Pallavi
A1 Zhao, Haitian
A1 Papoin, Julien
A1 Chatterjee, Prodyot K.
A1 Christen, Erica
A1 Metz, Christine N.
A1 Blanc, Lionel
A1 Campagne, Fabien
A1 Marambaud, Philippe
YR 2017
UL http://biorxiv.org/content/early/2017/05/13/137737.abstract
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.