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Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models
Santiago Ruiz, … , Fabien Campagne, Philippe Marambaud
Santiago Ruiz, … , Fabien Campagne, Philippe Marambaud
Published November 5, 2019
Citation Information: J Clin Invest. 2020;130(2):942-957. https://doi.org/10.1172/JCI127425.
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Research Article Cell biology Vascular biology

Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

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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.

Authors

Santiago Ruiz, Haitian Zhao, Pallavi Chandakkar, Julien Papoin, Hyunwoo Choi, Aya Nomura-Kitabayashi, Radhika Patel, Matthew Gillen, Li Diao, Prodyot K. Chatterjee, Mingzhu He, Yousef Al-Abed, Ping Wang, Christine N. Metz, S. Paul Oh, Lionel Blanc, Fabien Campagne, Philippe Marambaud

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Figure 9

Siro prevents mTOR overactivation, and Nin blocks overactivated VEGFR2 in tBMP9/10ib mice.

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Siro prevents mTOR overactivation, and Nin blocks overactivated VEGFR2 i...
(A–F) Control (CTRL) and tBMP9/10ib mice were treated with DMSO and Siro (A–C) or Nin (D–F). Protein homogenates of whole liver from P6 mice (A) and of liver ECs isolated from P9 mice (D) were analyzed by Western blot using antibodies directed against the indicated proteins. Scatter plots show areas positive for p-S6 (B) and p-VEGFR2 (E) analyzed by IHC in the retina of P6 CTRL and tBMP9/10ib mice treated with DMSO and Siro (B) or Nin (E), expressed as a percentage of the retinal vascular area occupied by immunofluorescence staining. Data represent mean ± SEM (n = 4, 3, and 3 mice for the CTRL, DMSO, and Siro [B] or Nin [E] groups, respectively); p-S6 analysis: Kruskal-Wallis test, post hoc Dunn’s multiple-comparisons test; p-VEGFR2 analysis: 1-way ANOVA, Tukey’s multiple-comparisons test. ***P < 0.001; ****P < 0.0001. Representative immunofluorescence images show P6 retinas from tBMP9/10ib mice treated as in B and E stained with fluorescent isolectin B4 (green, C and F), anti-p-S6 (magenta, C), anti–p-VEGFR2 (red, F), and anti-Erg (white, F) antibodies. Scale bars: 100 μm (C) and 50 μm (F).
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