ArticleThe Journal of clinical investigation2020
Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 84 citations in OpenAlex.
- Effect of oral nintedanib vs placebo on epistaxis in hereditary hemorrhagic telangiectasia: the EPICURE multicenter randomized double-blind trial.Angiogenesis · 2024Trial
- Loss of Smad4 drives vascular malformations via c-KIT-dependent high-fluid shear stress mimicry.The Journal of clinical investigation · 2026Article
- 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
- ActIIR inhibition improves motor outcome and preserves muscle fibers after experimental autoimmune neuritis.Acta neuropathologica communications · 2026Article
- Modeling Somatic Second-Hit Mutations in Novel Mouse Models of Hereditary Hemorrhagic Telangiectasia.bioRxiv : the preprint server for biology · 2026Article
- Effects of Nintedanib on Orofacial Fibroblasts and Myoblasts.Biomolecules · 2026Article
- Epigenome-wide DNA methylation profiling in aneurysmal subarachnoid hemorrhage and delayed ischemic neurologic deficit: a prospective observational study.International journal of surgery (London, England) · 2026Observational
- Article
- PI3K/AKT/mTOR axis in vascular malformations: from molecular insights to targeted clinical trials.Orphanet journal of rare diseases · 2025Review
- Epistaxis Prevention, Treatment, and Future Perspectives for Hereditary Hemorrhagic Telangiectasia.Journal of clinical medicine · 2025Review
- 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
- Article
- The Role of Somatic Mutation in Hereditary Hemorrhagic Telangiectasia Pathogenesis.Journal of clinical medicine · 2025Review
- Gastrointestinal Bleeding in Hereditary Hemorrhagic Telangiectasia Accompanied with Very Severe Thrombocytopenia.The American journal of case reports · 2025Article
- From bench to bedside: murine models of inherited and sporadic brain arteriovenous malformations.Angiogenesis · 2025Review
- Genetic and pharmacological targeting of mTORC1 in mouse models of arteriovenous malformation expose non-cell autonomous signalling in HHT.Angiogenesis · 2024Article
- Alk1/Endoglin signaling restricts vein cell size increases in response to hemodynamic cues.Angiogenesis · 2024Article
- Potential and emerging therapeutics for HHT.Hematology. American Society of Hematology. Education Program · 2024Review
Corrections and comments
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Authors and funding
18 authors at 6 institutions in 3 countries.
Funding
Abstract
Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs - including in HHT patient blood outgrowth ECs - and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.