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

Authors

Hyunwoo Choi, Barrow Aneurysm & AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.
Bo-Gyeong Kim, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Gaetbeol-Ro, Yeonsu-Gu, 21999, Incheon, Republic of Korea.
Yong Hwan Kim, Barrow Aneurysm & AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.
Se-Jin Lee, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Young Jae Lee, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Gaetbeol-Ro, Yeonsu-Gu, 21999, Incheon, Republic of Korea. leeyj@gachon.ac.kr.
S Paul Oh, Barrow Aneurysm & AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA. ohp@barrowneuro.org.

Document Type

Article

Abstract

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.

Keywords

Arteriovenous malformation, Bone morphogenetic protein 10, Bone morphogenetic protein 9, Endoglin, Hereditary hemorrhagic telangiectasia

Medical Subject Headings

Animals; Mice; Growth Differentiation Factor 2 (genetics, metabolism); Endothelial Cells (metabolism); Bone Morphogenetic Proteins (genetics); Telangiectasia, Hereditary Hemorrhagic (metabolism); Arteriovenous Malformations (pathology); Mice, Knockout; Activin Receptors, Type II (genetics, metabolism)

Publication Date

2-1-2023

Publication Title

Angiogenesis

E-ISSN

1573-7209

Volume

26

Issue

1

First Page

167

Last Page

186

PubMed ID

36348215

Digital Object Identifier (DOI)

10.1007/s10456-022-09859-0

Recommended Citation

Choi, Hyunwoo; Kim, Bo-Gyeong; Kim, Yong Hwan; Lee, Se-Jin; Lee, Young Jae; and Oh, S Paul, "BMP10 functions independently from BMP9 for the development of a proper arteriovenous network" (2023). Translational Neuroscience. 2242.
https://scholar.barrowneuro.org/neurobiology/2242