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BMP10 functions independently from BMP9 for the development of a proper arteriovenous network

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-β (TGF-β) family signaling: endoglin (ENG),...

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Autores principales: Choi, Hyunwoo, Kim, Bo-Gyeong, Kim, Yong Hwan, Lee, Se-Jin, Lee, Young Jae, Oh, S. Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Netherlands 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9908740/
https://www.ncbi.nlm.nih.gov/pubmed/36348215
http://dx.doi.org/10.1007/s10456-022-09859-0
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author Choi, Hyunwoo
Kim, Bo-Gyeong
Kim, Yong Hwan
Lee, Se-Jin
Lee, Young Jae
Oh, S. Paul
author_facet Choi, Hyunwoo
Kim, Bo-Gyeong
Kim, Yong Hwan
Lee, Se-Jin
Lee, Young Jae
Oh, S. Paul
author_sort Choi, Hyunwoo
collection PubMed
description Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-β (TGF-β) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9-KO, and Bmp9/10-double KO (dKO) mice. Bmp10-iKO and Bmp9/10-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9-KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10-iKO and Bmp9/10-dKO mice was detected. Bmp9/10-dKO mice exhibited the lethality and vascular malformation similar to Bmp10-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10-dKO and endothelial-specific Eng-iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10456-022-09859-0.
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spelling pubmed-99087402023-02-10 BMP10 functions independently from BMP9 for the development of a proper arteriovenous network Choi, Hyunwoo Kim, Bo-Gyeong Kim, Yong Hwan Lee, Se-Jin Lee, Young Jae Oh, S. Paul Angiogenesis Original Paper Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-β (TGF-β) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9-KO, and Bmp9/10-double KO (dKO) mice. Bmp10-iKO and Bmp9/10-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9-KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10-iKO and Bmp9/10-dKO mice was detected. Bmp9/10-dKO mice exhibited the lethality and vascular malformation similar to Bmp10-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10-dKO and endothelial-specific Eng-iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10456-022-09859-0. Springer Netherlands 2022-11-08 2023 /pmc/articles/PMC9908740/ /pubmed/36348215 http://dx.doi.org/10.1007/s10456-022-09859-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Paper
Choi, Hyunwoo
Kim, Bo-Gyeong
Kim, Yong Hwan
Lee, Se-Jin
Lee, Young Jae
Oh, S. Paul
BMP10 functions independently from BMP9 for the development of a proper arteriovenous network
title BMP10 functions independently from BMP9 for the development of a proper arteriovenous network
title_full BMP10 functions independently from BMP9 for the development of a proper arteriovenous network
title_fullStr BMP10 functions independently from BMP9 for the development of a proper arteriovenous network
title_full_unstemmed BMP10 functions independently from BMP9 for the development of a proper arteriovenous network
title_short BMP10 functions independently from BMP9 for the development of a proper arteriovenous network
title_sort bmp10 functions independently from bmp9 for the development of a proper arteriovenous network
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9908740/
https://www.ncbi.nlm.nih.gov/pubmed/36348215
http://dx.doi.org/10.1007/s10456-022-09859-0
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