title: Osteopontin, a Key Mediator Expressed by Senescent Pulmonary Vascular Cells in Pulmonary Hypertension.
abstract: Senescent pulmonary artery smooth muscle cells (PA-SMCs) may contribute to the pathogenesis of pulmonary hypertension by producing secreted factors. The aim of this study was to explore the role in pulmonary hypertension of extracellular matrix proteins released by senescent PA-SMCs.
  
  
  
  Polymerase chain reaction array analysis of human PA-SMCs undergoing replicative senescence revealed osteopontin upregulation, which mediated the stimulatory effect of senescent PA-SMC media and matrix on PA-SMC growth and migration. Osteopontin was upregulated in lungs from patients with chronic obstructive pulmonary disease or idiopathic pulmonary arterial hypertension. Prominent osteopontin immunostaining was noted in PA-SMCs that also stained for p16 at sites of vascular hypertrophy, and lung osteopontin levels correlated closely with age. Compared with younger mice, 1-year-old mice displayed higher lung osteopontin levels, right ventricular systolic pressure, pulmonary vessel muscularization, and numbers of PA-SMCs stained for p16 or p21 and also for osteopontin. No such changes with age were observed in osteopontin(-/-) mice, which developed attenuated pulmonary hypertension during hypoxia. Compared with cultured PA-SMCs from young mice, PA-SMCs from 1-year-old mice grew faster; a similar fast growth rate was seen with PA-SMCs from young mice stimulated by matrix or media from old mice. Differences between old/young mouse PA-SMC growth rates were suppressed by antiosteopontin antibodies. PA-SMCs from osteopontin(-/-) mice grew more slowly than did wild-type PA-SMCs; they were stimulated by wild-type PA-SMCs media and matrix, and this effect was stronger with PA-SMCs from older versus younger mice.
  
  
  
  Osteopontin is a key mediator released by senescent PA-SMCs and contributing to pulmonary hypertension progression.
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Mirna
authors.initials: M
authors.lastname: Saker
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lipskaia
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Marcos
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Shariq
authors.initials: S
authors.lastname: Abid
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Aurelien
authors.initials: A
authors.lastname: Parpaleix
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Amal
authors.initials: A
authors.lastname: Houssaini
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Girard
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Hiba
authors.initials: H
authors.lastname: Noureddine
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Boyer
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Nora
authors.initials: N
authors.lastname: Vienney
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Valerie
authors.initials: V
authors.lastname: Amsellem
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Marguerit
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Maitre
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Derumeaux
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois-Rande
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Claude
authors.initials: C
authors.lastname: Jourdan-Lesaux
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Marion
authors.initials: M
authors.lastname: Delcroix
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium.
authors.forename: Rozenn
authors.initials: R
authors.lastname: Quarck
authors.affiliation: From the INSERM U955, Département de Physiologie (M.S., L.L., E.M., S.A., A.P., A.H., H.N., L.B., N.V., V.A., L.M., B.M., G.D., C.J.-L., S.A.) and Service de Cardiologie (J.-L.D.-R.), Hôpital Henri Mondor, Université Paris-Est Créteil, France; Institut Mutualiste Montsouris, Département Anatomopathologie, Paris, France (P.V., P.G.); and Respiratory Division, University Hospitals of Leuven (M.D., R.Q.) and Department of Clinical and Experimental Medicine (M.D., R.Q.), University of Leuven, Leuven, Belgium. serge.adnot@inserm.fr.
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005838:Genotype; D006439:Hemodynamics; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D015854:Up-Regulation; D016278:Ventricular Function, Right
chemical_list: D016326:Extracellular Matrix Proteins; C506895:SPP1 protein, human; C506896:Spp1 protein, mouse; D053495:Osteopontin
keywords: biological process; cell proliferation; extracellular matrix; osteopontin; pulmonary hypertension