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- Title
Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models.
- Authors
Ruiz, Santiago; Zhao, Haitian; Chandakkar, Pallavi; Papoin, Julien; Hyunwoo Choi; Nomura-Kitabayashi, Aya; Patel, Radhika; Gillen, Matthew; Li Diao; Chatterjee, Prodyot K.; Mingzhu He; Al-Abed, Yousef; Ping Wang; Metz, Christine N.; Oh, S. Paul; Blanc, Lionel; Campagne, Fabien; Marambaud, Philippe; Choi, Hyunwoo; Diao, Li
- 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.
- Subjects
HEREDITARY hemorrhagic telangiectasia; GASTROINTESTINAL hemorrhage; PATHOLOGY; ORAL mucosa; RAPAMYCIN; PROTEIN-tyrosine kinases; ERYTHROPOIETIN receptors; BIOLOGICAL models; RESEARCH; INDOLE compounds; ANIMAL experimentation; RESEARCH methodology; CELL receptors; BONE morphogenetic proteins; EVALUATION research; MEDICAL cooperation; CELLULAR signal transduction; COMPARATIVE studies; RESEARCH funding; EPITHELIAL cells; CARRIER proteins; MICE; PHARMACODYNAMICS
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 2, p942
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI127425