title: Alk2/ACVR1 and Alk3/BMPR1A Provide Essential Function for Bone Morphogenetic Protein-Induced Retinal Angiogenesis.
abstract: Increasing evidence suggests that bone morphogenetic protein (BMP) signaling regulates angiogenesis. Here, we aimed to define the function of BMP receptors in regulating early postnatal angiogenesis by analysis of inducible, endothelial-specific deletion of the BMP receptor componentsBmpr2(BMP type 2 receptor),Alk1(activin receptor-like kinase 1),Alk2, andAlk3in mouse retinal vessels.
  
  
  
  Expression analysis of several BMP ligands showed that proangiogenic BMP ligands are highly expressed in postnatal retinas. Consistently, BMP receptors are also strongly expressed in retina with a distinct pattern. To assess the function of BMP signaling in retinal angiogenesis, we first generated mice carrying an endothelial-specific inducible deletion ofBmpr2. Postnatal deletion ofBmpr2in endothelial cells substantially decreased the number of angiogenic sprouts at the vascular front and branch points behind the front, leading to attenuated radial expansion. To identify critical BMPR1s (BMP type 1 receptors) associated with BMPR2 in retinal angiogenesis, we generated endothelial-specific inducible deletion of 3 BMPR1s abundantly expressed in endothelial cells and analyzed the respective phenotypes. Among these, endothelial-specific deletion of eitherAlk2/acvr1orAlk3/Bmpr1acaused a delay in radial expansion, reminiscent of vascular defects associated with postnatal endothelial-specific deletion of BMPR2, suggesting that ALK2/ACVR1 and ALK3/BMPR1A are likely to be the critical BMPR1s necessary for proangiogenic BMP signaling in retinal vessels.
  
  
  
  Our data identify BMP signaling mediated by coordination of ALK2/ACVR1, ALK3/BMPR1A, and BMPR2 as an essential proangiogenic cue for retinal vessels.
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Heon-Woo
authors.initials: HW
authors.lastname: Lee
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Diana C
authors.initials: DC
authors.lastname: Chong
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Roxana
authors.initials: R
authors.lastname: Ola
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: William P
authors.initials: WP
authors.lastname: Dunworth
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Stryder
authors.initials: S
authors.lastname: Meadows
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Jun
authors.initials: J
authors.lastname: Ka
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Kaartinen
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Yibing
authors.initials: Y
authors.lastname: Qyang
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Ondine
authors.initials: O
authors.lastname: Cleaver
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.). bautch@unc.edu anne.eichmann@yale.edu suk-won.jin@yale.edu sukwonjin@gist.ac.kr.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bautch
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
authors.affiliation: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).
authors.forename: Suk-Won
authors.initials: SW
authors.lastname: Jin
mesh_terms: D030201:Activin Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000172:deficiency / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D008024:Ligands; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012161:Retinal Artery / Q000187:drug effects* / Q000378:metabolism; D015861:Retinal Neovascularization; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D008024:Ligands; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498943:Acvr1 protein, mouse; C498931:Acvrl1 protein, mouse; C498212:Bmpr1a protein, mouse; C498219:Bmpr2 protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: BMP signaling; angiogenesis; retina; vertebrate development