title: BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II.
abstract: ALK1 (ACVRL1) is a member of the TGFβ receptor family and is expressed predominantly by arterial endothelial cells (EC). Mutations in ACVRL1 are responsible for hereditary hemorrhagic telangiectasia type 2 (HHT2), a disease manifesting as fragile vessels, capillary overgrowth, and numerous arterio-venous malformations. Arterial EC also express EphrinB2, which has multiple roles in vascular development and angiogenesis and is known to be reduced in ACVRL1 knockout mice. Using an in vitro angiogenesis model we find that the Alk1 ligand BMP9 induces EphrinB2 in EC, and this is entirely dependent on expression of Alk1 and at least one of the co-receptors BMPRII or ActRII. BMP9 induces both ID1 and ID3, and both are necessary for full induction of EphrinB2. Loss of Alk1 or EphrinB2 results in increased arterial-venous anastomosis, while loss of Alk1 but not EphrinB2 results in increased VEGFR2 expression and enhanced capillary sprouting. Conversely, BMP9 blocks EC sprouting and this is dependent on Alk1, BMPRII/ActRII and ID1/ID3. Finally, notch signaling overcomes the loss of Alk1-restoring EphrinB2 expression in EC, and curbing excess sprouting. Thus, in an in vitro model of HHT2, loss of Alk1 blocks BMP9 signaling, resulting in reduced EphrinB2 expression, enhanced VEGFR2 expression, and misregulated EC sprouting and anastomosis.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Jai-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Peacock
authors.forename: Steven C
authors.initials: SC
authors.lastname: George
authors.forename: Christopher C W
authors.initials: CC
authors.lastname: Hughes
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics* / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism*; D055427:Growth Differentiation Factor 2 / Q000502:physiology*; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D036388:Ephrin-B2; D055427:Growth Differentiation Factor 2; D051796:Inhibitor of Differentiation Proteins; D051880:Receptors, Notch; C067679:Idb3 protein, mouse; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II; C425585:activin receptor type II-A