Heon-Woo Lee1, Diana C Chong1, Roxana Ola1, William P Dunworth1, Stryder Meadows1, Jun Ka1, Vesa M Kaartinen1, Yibing Qyang1, Ondine Cleaver1, Victoria L Bautch2, Anne Eichmann1, Suk-Won Jin1. 1. 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.). 2. 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.
Abstract
OBJECTIVE: 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 components Bmpr2 (BMP type 2 receptor), Alk1 (activin receptor-like kinase 1), Alk2, and Alk3 in mouse retinal vessels. APPROACH AND RESULTS: 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 of Bmpr2. Postnatal deletion of Bmpr2 in 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 either Alk2/acvr1 or Alk3/Bmpr1a caused 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. CONCLUSIONS: Our data identify BMP signaling mediated by coordination of ALK2/ACVR1, ALK3/BMPR1A, and BMPR2 as an essential proangiogenic cue for retinal vessels.
OBJECTIVE: 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 components Bmpr2 (BMP type 2 receptor), Alk1 (activin receptor-like kinase 1), Alk2, and Alk3 in mouse retinal vessels. APPROACH AND RESULTS: 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 of Bmpr2. Postnatal deletion of Bmpr2 in 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 either Alk2/acvr1 or Alk3/Bmpr1a caused 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. CONCLUSIONS: Our data identify BMP signaling mediated by coordination of ALK2/ACVR1, ALK3/BMPR1A, and BMPR2 as an essential proangiogenic cue for retinal vessels.
Authors: P ten Dijke; H Yamashita; T K Sampath; A H Reddi; M Estevez; D L Riddle; H Ichijo; C H Heldin; K Miyazono Journal: J Biol Chem Date: 1994-06-24 Impact factor: 5.157
Authors: Z Gu; E M Reynolds; J Song; H Lei; A Feijen; L Yu; W He; D T MacLaughlin; J van den Eijnden-van Raaij; P K Donahoe; E Li Journal: Development Date: 1999-06 Impact factor: 6.868
Authors: David M Wiley; Jun-Dae Kim; Jijun Hao; Charles C Hong; Victoria L Bautch; Suk-Won Jin Journal: Nat Cell Biol Date: 2011-05-15 Impact factor: 28.824
Authors: Irene Maria Aspalter; Emma Gordon; Alexandre Dubrac; Anan Ragab; Jarek Narloch; Pedro Vizán; Ilse Geudens; Russell Thomas Collins; Claudio Areias Franco; Cristina Luna Abrahams; Gavin Thurston; Marcus Fruttiger; Ian Rosewell; Anne Eichmann; Holger Gerhardt Journal: Nat Commun Date: 2015-06-17 Impact factor: 14.919
Authors: Max A Tischfield; Caroline D Robson; Nicole M Gilette; Shek Man Chim; Folasade A Sofela; Michelle M DeLisle; Alon Gelber; Brenda J Barry; Sarah MacKinnon; Linda R Dagi; Jeremy Nathans; Elizabeth C Engle Journal: Dev Cell Date: 2017-08-30 Impact factor: 12.270
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311