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HHT is caused by mutations in genes encoding major constituents for transforming growth factor-\u03b2 (TGF-\u03b2) 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 <jats:italic>Bmp10<\/jats:italic> conditional knockout mouse strain. We examined whether global <jats:italic>Bmp10<\/jats:italic>-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, <jats:italic>Bmp9<\/jats:italic>-KO, and <jats:italic>Bmp9\/10<\/jats:italic>-double KO (dKO) mice. <jats:italic>Bmp10<\/jats:italic>-iKO and <jats:italic>Bmp9\/10<\/jats:italic>-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while <jats:italic>Bmp9<\/jats:italic>-KO did not display any noticeable vascular defects. <jats:italic>Bmp10<\/jats:italic> deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of <jats:italic>Bmp10<\/jats:italic>-iKO and <jats:italic>Bmp9\/10<\/jats:italic>-dKO mice was detected. <jats:italic>Bmp9\/10<\/jats:italic>-dKO mice exhibited the lethality and vascular malformation similar to <jats:italic>Bmp10<\/jats:italic>-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in <jats:italic>Bmp9\/10<\/jats:italic>-dKO and endothelial-specific <jats:italic>Eng<\/jats:italic>-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.<\/jats:p>","DOI":"10.1007\/s10456-022-09859-0","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T21:02:48Z","timestamp":1667941368000},"page":"167-186","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["BMP10 functions independently from BMP9 for the development of a proper arteriovenous network"],"prefix":"10.1007","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2615-1961","authenticated-orcid":false,"given":"Hyunwoo","family":"Choi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo-Gyeong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1244-4269","authenticated-orcid":false,"given":"Yong Hwan","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se-Jin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3841-1994","authenticated-orcid":false,"given":"Young Jae","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3833-0342","authenticated-orcid":false,"given":"S. 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