ArticleHuman molecular genetics2017
Tacrolimus rescues the signaling and gene expression signature of endothelial ALK1 loss-of-function and improves HHT vascular pathology.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed.
- Nitazoxanide activates BMP9-ALK1-SMAD signaling cascade and improves HHT vascular pathology.bioRxiv : the preprint server for biology · 2026Article
- An angiopoietin-2 vaccine improves arteriovenous malformation pathology in hereditary hemorrhagic telangiectasia mice.Blood vessels, thrombosis & hemostasis · 2026Article
- The role of Id genes on pulmonary hypertension development in left heart failure.American heart journal plus : cardiology research and practice · 2026Article
- An angiopoietin-2 vaccine improves arteriovenous malformation pathology in hereditary hemorrhagic telangiectasia mice.bioRxiv : the preprint server for biology · 2025Article
- ALK1-BMPRII agonism by clustering bispecific antibodies treats hereditary hemorrhagic telangiectasia.bioRxiv : the preprint server for biology · 2025Article
- The Role of Somatic Mutation in Hereditary Hemorrhagic Telangiectasia Pathogenesis.Journal of clinical medicine · 2025Review
- From bench to bedside: murine models of inherited and sporadic brain arteriovenous malformations.Angiogenesis · 2025Review
- Updates on the Pathogenesis and Therapeutic Approaches for Hereditary Hemorrhagic Telangiectasia.Current vascular pharmacology · 2025Review
- CDK6-mediated endothelial cell cycle acceleration drives arteriovenous malformations in hereditary hemorrhagic telangiectasia.Nature cardiovascular research · 2024Article
- Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.American journal of human genetics · 2024Article
- The Role of Thalidomide and Its Analogs in the Treatment of Hereditary Hemorrhagic Telangiectasia: A Systematic Review.Journal of clinical medicine · 2024Review
- Defining the Role of Oral Pathway Inhibitors as Targeted Therapeutics in Arteriovenous Malformation Care.Biomedicines · 2024Review
- Induced Endothelial Cell Cycle Arrest Prevents Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.Circulation · 2024Article
- Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances.The Journal of clinical investigation · 2024Review
- Tacrolimus as a Promising Drug for Epistaxis and Gastrointestinal Bleeding in HHT.Journal of clinical medicine · 2023Article
- ANG2 Blockade Diminishes Proangiogenic Cerebrovascular Defects Associated With Models of Hereditary Hemorrhagic Telangiectasia.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
- Efficacy and Safety of Tacrolimus as Treatment for Bleeding Caused by Hereditary Hemorrhagic Telangiectasia: An Open-Label, Pilot Study.Journal of clinical medicine · 2022Article
- A case of hereditary hemorrhagic telangiectasia and literature review.Journal of clinical laboratory analysis · 2022Review
- Rethinking growth factors: the case of BMP9 during vessel maturation.Vascular biology (Bristol, England) · 2022Review
- The relationship between periodontal status and hyperglycemia after kidney transplantation.Clinical oral investigations · 2022Article
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10 authors.
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Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a highly debilitating and life-threatening 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 bone morphogenetic protein 9 (BMP9)-ALK1-Smad1/5/8 signaling, interventions aimed at activating this pathway are of therapeutic value. We interrogated the whole-transcriptome in human umbilical vein ECs (HUVECs) and found that ALK1 signaling inhibition was associated with a specific pro-angiogenic gene expression signature, which included a significant elevation of DLL4 expression. By screening the NIH clinical collections of FDA-approved drugs, we identified tacrolimus (FK-506) as the most potent activator of ALK1 signaling in BMP9-challenged C2C12 reporter cells. In HUVECs, tacrolimus activated Smad1/5/8 and opposed 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 vascular endothelial growth factor, a major driver of angiogenesis. 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 signaling in C2C12 cells expressing BMP9-unresponsive ALK1 HHT mutants and in HHT patient blood outgrowth ECs. Tacrolimus repurposing has therefore therapeutic potential in HHT.
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