title: Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium.
abstract: The importance of morphogenetic proteins (BMPs) and their antagonists in vascular development is increasingly being recognized. BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein (MGP) and crossveinless 2 (CV2), both induced by the activin receptor like-kinase 1 (ALK1) when stimulated by BMP-9. In this study, however, we show that CV2 preferentially binds and inhibits BMP-9 thereby providing strong feedback inhibition for BMP-9/ALK1 signaling rather than for BMP-4/ALK2 signaling. CV2 disrupts complex formation involving ALK2, ALK1, BMP-4, and BMP-9 required for the induction of both BMP antagonists. It also limits VEGF expression, proliferation, and tube formation in ALK1-expressing endothelial cells. In vivo, CV2 deficiency translates into a dysregulation of vascular BMP signaling, resulting in an abnormal endothelium with increased endothelial cellularity and expression of lineage markers for mature endothelial cells. Thus, mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium.
authors.affiliation: Division of Cardiology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095-1679, USA.
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Yao
authors.forename: Medet
authors.initials: M
authors.lastname: Jumabay
authors.forename: Albert
authors.initials: A
authors.lastname: Ly
authors.forename: Melina
authors.initials: M
authors.lastname: Radparvar
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Wang
authors.forename: Raushan
authors.initials: R
authors.lastname: Abdmaulen
authors.forename: Kristina I
authors.initials: KI
authors.lastname: Boström
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D055427:Growth Differentiation Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding / Q000187:drug effects; D013379:Substrate Specificity
chemical_list: C525809:BMP4 protein, human; C476724:BMPER protein, human; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D055427:Growth Differentiation Factor 2; C425423:ACVR1 protein, human; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II