Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Abstract

Hereditary hemorrhagic telangiectasia (HHT), or Rendu-OslerWeber syndrome, is an autosomal-dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations in internal organs. Patients show severe epistaxis, and/or gastrointestinal bleeding, both of which notably interfere with their quality of life. There are two predominant types of HHT caused by mutations in endoglin (ENG) and ACVRL1/activin receptor-like kinase 1 (ALK1) genes, named HHT1 and HHT2, respectively. ENG and ALK1 code for proteins involved in the transforming growth factor (TGF)-␤1 signaling pathway, and it is widely accepted that HHT pathogenicity results from haploinsufficiency. No cure for HHT has been found, so identification of drugs able to increase the expression of these genes is essential when proposing new therapies. We report the efficacy of tacrolimus (FK506) in increasing ENG and ALK1 expression. The rationale comes from a case report of a patient with HHT who received a liver transplantation after hepatic failure due to a liver arteriovenous malformation. The liver was transplanted, and the immunosuppressor FK506 was used to prevent the rejection. After the first month of FK506 treatment, the internal and external telangiectases, epistaxes, and anemia disappeared. Here, we find that the immunosuppressor FK506 increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells and enhances the TGF-␤1/ALK1 signaling pathway and endothelial cell functions like tubulogenesis and migration. These results suggest that the mechanism of action of FK506 involves a partial correction of endoglin and ALK1 haploinsufficiency and may therefore be an interesting drug for use in patients with HHT who undergo transplantation.

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

“…FK506 also increases EC expression of ALK1 and endoglin (60). As loss-of-function mutations in these genes are observed in PAH associated with hemorrhagic telangiectasia (HHT), FK506 could also be of potential benefit in patients with this disorder.…”

“…As loss-of-function mutations in these genes are observed in PAH associated with hemorrhagic telangiectasia (HHT), FK506 could also be of potential benefit in patients with this disorder. In fact, FK506 was given following liver transplant in a patient with HHT who had multiple arteriovenous malformations, and it was noted that internal and external telangiectases, epistaxes, and anemia disappeared, suggesting that the mechanism of action of FK506 involved partial correction of endoglin and ALK1 haploinsufficiency (60).…”

ALK2 and BMPR2 knockdown and endothelin-1 production by pulmonary microvascular endothelial cells

“…Activation of the ALK2 receptor by FK506 has previously been shown to increase phospho SMAD1/5, even in the absence of BMPs (Song et al, 2010). FK506 does not act through SMAD2/3 in microvascular endothelial cells (Albinana et al, 2011). Moreover, FK506 stimulates ET-1 production by rat mesangial cells and human umbilical vein endothelial cells, and it increases urinary and plasma endothelin levels after transplantation in humans (Goodall et al, 1995;Marsen et al, 2000;Slowinski et al, 2002;Textor et al, 1995).…”

Genetic and Molecular Basis for Hereditary Hemorrhagic Telangiectasia

“…For example, the protein FKBP12 binds to TGF-b family type I receptors and restricts phosphorylation and thus activation; the drug FK506 (tacrolimus) inhibits this interaction, thereby enhancing the receptors' kinase activity [125]. FK506 also enhances ALK1 and ENG expressions in cultured human endothelial cells [126], and there is an anecdotal report of a single HHT patient who, after liver transplant, experienced profound regression of telangiectasias while taking a cocktail of drugs including FK506 [127]. Notably, FK506 rescues pulmonary arterial hypertension resulting from inadequate BMP signaling in mouse and rat models [128 •• ], supporting the notion that this drug may be effective in HHT.…”