title: A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10.
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 their newborns share the same immunity through the transfer of maternal antibodies during lactation. 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 blood circulation of lactationally-exposed neonatal pups. Strikingly, pups receiving anti-BMP9/10 antibodies via lactation 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.
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ruiz
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Haitian
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chandakkar
authors.affiliation: Center for Biomedical Sciences, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Prodyot K
authors.initials: PK
authors.lastname: Chatterjee
authors.affiliation: Center for Autoimmune and Musculoskeletal Disorders, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Papoin
authors.affiliation: Center for Autoimmune and Musculoskeletal Disorders, The Feinstein Institute for Medical Research, Manhasset, NY, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Blanc
authors.affiliation: Center for Biomedical Sciences, The Feinstein Institute for Medical Research, Manhasset, NY, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, USA.
authors.forename: Christine N
authors.initials: CN
authors.lastname: Metz
authors.affiliation: The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, The Weill Cornell Medical College, New York, NY, USA.|Department of Physiology and Biophysics, The Weill Cornell Medical College, New York, NY, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Campagne
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D019138:Antibodies, Blocking / Q000097:blood / Q000494:pharmacology*; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular; D005260:Female; D055427:Growth Differentiation Factor 2 / Q000276:immunology*; D007774:Lactation / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000276:immunology; D012171:Retinal Vessels / Q000473:pathology; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000276:immunology / Q000473:pathology*
chemical_list: D042702:Angiopoietin-2; D019138:Antibodies, Blocking; C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; D055427:Growth Differentiation Factor 2