title: Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations.
abstract: OBJECTIVE
  To determine the role of Gja5 that encodes for the gap junction protein connexin40 in the generation of arteriovenous malformations in the hereditary hemorrhagic telangiectasia type 2 (HHT2) mouse model.
  
  
  RESULTS
  We identified GJA5 as a target gene of the bone morphogenetic protein-9/activin receptor-like kinase 1 signaling pathway in human aortic endothelial cells and importantly found that connexin40 levels were particularly low in a small group of patients with HHT2. We next took advantage of the Acvrl1(+/-) mutant mice that develop lesions similar to those in patients with HHT2 and generated Acvrl1(+/-); Gja5(EGFP/+) mice. Gja5 haploinsufficiency led to vasodilation of the arteries and rarefaction of the capillary bed in Acvrl1(+/-) mice. At the molecular level, we found that reduced Gja5 in Acvrl1(+/-) mice stimulated the production of reactive oxygen species, an important mediator of vessel remodeling. To normalize the altered hemodynamic forces in Acvrl1(+/-); Gja5(EGFP/+) mice, capillaries formed transient arteriovenous shunts that could develop into large malformations when exposed to environmental insults.
  
  
  CONCLUSIONS
  We identified GJA5 as a potential modifier gene for HHT2. Our findings demonstrate that Acvrl1 haploinsufficiency combined with the effects of modifier genes that regulate vessel caliber is responsible for the heterogeneity and severity of the disease. The mouse models of HHT have led to the proposal that 3 events-heterozygosity, loss of heterozygosity, and angiogenic stimulation-are necessary for arteriovenous malformation formation. Here, we present a novel 3-step model in which pathological vessel caliber and consequent altered blood flow are necessary events for arteriovenous malformation development.
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Gkatzis
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Jérémy
authors.initials: J
authors.lastname: Thalgott
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Damien
authors.initials: D
authors.lastname: Dos-Santos-Luis
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Sabrina
authors.initials: S
authors.lastname: Martin
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Noël
authors.initials: N
authors.lastname: Lamandé
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Marie France
authors.initials: MF
authors.lastname: Carette
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Frans
authors.initials: F
authors.lastname: Disch
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Repke J
authors.initials: RJ
authors.lastname: Snijder
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Cornelius J
authors.initials: CJ
authors.lastname: Westermann
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Johannes J
authors.initials: JJ
authors.lastname: Mager
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Lucile
authors.initials: L
authors.lastname: Miquerol
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Helen M
authors.initials: HM
authors.lastname: Arthur
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.).
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.affiliation: From the Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands (K.G., C.L.M.); CNRS Unité mixte de recherche 7241/INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris cedex 05, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); MEMOLIFE Laboratory of Excellence, Paris Sciences et Lettres Research University, Paris, France (J.T., D.D.-S.-L., S.M., N.L., F.L.); Department of Radiology, AP-HP, Tenon Hospital, Paris, France (M.F.C.); Sorbonne Universités, UPMC University, Paris, France (M.F.C.); St. Antonius Hospital, Nieuwegein, The Netherlands (F.D., R.J.S., C.J.W., J.J.M.); Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (S.P.O.); Aix Marseille Université, CNRS IBDM UMR 7288, Marseille cedex 09, France (L.M.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (H.M.A.). franck.lebrin@college-de-france.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Lebrin
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001165:Arteriovenous Malformations / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology*; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006801:Humans; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D010641:Phenotype; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012171:Retinal Vessels / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014162:Transfection; D066253:Vascular Remodeling; D000097003:Gap Junction alpha-5 Protein
chemical_list: D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D017630:Connexins; D017382:Reactive Oxygen Species; D000097003:Gap Junction alpha-5 Protein; C425364:ACVRL1 protein, human; C498931:Acvrl1 protein, mouse
keywords: alpha-smooth muscle actin, mouse; arteriovenous malformations; connexin 40; erythrocyte; hereditary hemorrhagic telangiectasia