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A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10

Santiago Ruiz, Haitian Zhao, Pallavi Chandakkar, Prodyot K. Chatterjee, Lionel Blanc, Christine N. Metz, View ORCID ProfileFabien Campagne, View ORCID ProfilePhilippe Marambaud
doi: https://doi.org/10.1101/084889
Santiago Ruiz
1Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
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Haitian Zhao
1Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
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Pallavi Chandakkar
1Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
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Prodyot K. Chatterjee
2Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
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Lionel Blanc
3Center for Autoimmune and Musculoskeletal Disorder, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
4Hofstra Northwell School of Medicine, Hempstead, NY, USA.
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Christine N. Metz
2Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
4Hofstra Northwell School of Medicine, Hempstead, NY, USA.
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Fabien Campagne
5The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, The Weill Cornell Medical College, New York, NY, USA.
6Department of Physiology and Biophysics, The Weill Cornell Medical College, New York, NY, USA.
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  • ORCID record for Fabien Campagne
Philippe Marambaud
1Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
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  • ORCID record for Philippe Marambaud
  • For correspondence: PMaramba@northwell.edu
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ABSTRACT

Hereditary hemorrhagic telangiectasia (HHT) is a potentially life-threatening genetic vascular disorder caused by loss-of-function mutations in the genes encoding activin receptor-like kinase 1 (ALK1), endoglin, Smad4, and bone morphogenetic protein 9 (BMP9). Injections of mouse neonates with BMP9/10 blocking antibodies lead to HHT-like vascular defects in the postnatal retinal angiogenesis model. Mothers and newborns share the same immunity through the transfer of maternal antibodies during breastfeeding. Here, we investigated whether the transmammary delivery route could improve the ease and consistency of administering anti-BMP9/10 antibodies in the postnatal retinal angiogenesis model. We found that anti-BMP9/10 antibodies, when intraperitoneally injected into lactating dams, are efficiently transferred into the circulation of breastfed neonatal pups. Strikingly, pups receiving anti-BMP9/10 antibodies via breastfeeding displayed consistent and robust vascular pathology in the retina, which included hypervascularization and defects in arteriovenous specification, as well as the presence of multiple and massive arteriovenous malformations. Furthermore, RNA-Seq analyses of neonatal retinas identified an increase in the key pro-angiogenic factor, angiopoietin-2, as the most significant change in gene expression triggered by the transmammary delivery of anti-BMP9/10 antibodies. Transmammary-delivered BMP9/10 immunoblocking in the mouse neonatal retina is therefore a practical, noninvasive, reliable, and robust model of HHT vascular pathology.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 02, 2016.
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A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10
Santiago Ruiz, Haitian Zhao, Pallavi Chandakkar, Prodyot K. Chatterjee, Lionel Blanc, Christine N. Metz, Fabien Campagne, Philippe Marambaud
bioRxiv 084889; doi: https://doi.org/10.1101/084889
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A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10
Santiago Ruiz, Haitian Zhao, Pallavi Chandakkar, Prodyot K. Chatterjee, Lionel Blanc, Christine N. Metz, Fabien Campagne, Philippe Marambaud
bioRxiv 084889; doi: https://doi.org/10.1101/084889

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