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JGM, Animals, Mice, Growth Differentiation Factor 2, Endothelial Cells, Bone Morphogenetic Proteins, Telangiectasia, Hereditary Hemorrhagic, Arteriovenous Malformations, Mice, Knockout, Activin Receptors, Type II

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Angiogenesis. 2023;26(1):167-86







This work was supported by the US Department of Defense (PR161205), the US National Institutes of Health (R01 HL128525), the Leducq Foundation (ATTRACT), and Barrow Neurological Foun- dation to SPO; and the Korea Mouse Phenotyping Project (NRF- 2014M3A9D5A01073528) and Medical Research Center (MRC) Program (2021R1A5A2030333) of the National Research Foundation (NRF) funded by the Korean government (MSIT) to YJL, in part by the NRF funded by the Ministry of Education (2021R1I1A2042228) to YJL, and by Barrow Neurological Foundation Postdoctoral Fellow- ship to HC.


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.


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