title: Disseminated arterial calcification and enhanced myogenic response are associated with abcc6 deficiency in a mouse model of pseudoxanthoma elasticum.
abstract: OBJECTIVE
  Pseudoxanthoma elasticum is an inherited metabolic disorder resulting from ABCC6 gene mutations. It is characterized by progressive calcification and fragmentation of elastic fibers in the skin, retina, and the arterial wall. Despite calcium accumulation in the arteries of patients with pseudoxanthoma elasticum, functional consequences remain unknown. In the present study, we investigated arterial structure and function in Abcc6(-/-) mice, a model of the human disease.
  
  
  RESULTS
  Arterial calcium accumulation was evaluated using alizarin red stain and atomic absorption spectrometry. Expression of genes involved in osteochondrogenic differentiation was measured by polymerase chain reaction. Elastic arterial properties were evaluated by carotid echotracking. Vascular reactivity was evaluated using wire and pressure myography and remodeling using histomorphometry. Arterial calcium accumulation was 1.5- to 2-fold higher in Abcc6(-/-) than in wild-type mice. Calcium accumulated locally leading to punctuate pattern. Old Abcc6(-/-) arteries expressed markers of both osteogenic (Runx2, osteopontin) and chondrogenic lineage (Sox9, type II collagen). Abcc6(-/-) arteries displayed slight increase in arterial stiffness and vasoconstrictor tone in vitro tended to be higher in response to phenylephrine and thromboxane A2. Pressure-induced (myogenic) tone was significantly higher in Abcc6(-/-) arteries than in wild type. Arterial blood pressure was not significantly changed in Abcc6(-/-), despite higher variability.
  
  
  CONCLUSIONS
  Scattered arterial calcium depositions are probably a result of osteochondrogenic transdifferentiation of vascular cells. Lower elasticity and increased myogenic tone without major changes in agonist-dependent contraction evidenced in aged Abcc6(-/-) mice suggest a reduced control of local blood flow, which in turn may alter vascular homeostasis in the long term.
authors.affiliation: From the CNRS UMR 6214, INSERM U1083, l'UNAM (G.K., Y.L.C., E.V., L.G., B.T., G.L., D.H., L.M.) and Laboratoire de Pharmacologie-Toxicologie, l'UNAM, Université d'Angers (Y.M.), University Hospital Angers, Angers, France; INSERM, U1116 (A.P., C.L., P.L.), Université de Lorraine, Vandoeuvre-lès-Nancy, France; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI (O.L.S.); Molecular Ophthalmogenetics, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (T.G.G., A.A.B.); and Departments of Ophthalmology (A.A.B.) and Clinical Genetics (A.A.B.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Gilles
authors.initials: G
authors.lastname: Kauffenstein
authors.forename: A
authors.initials: A
authors.lastname: Pizard
authors.forename: Y
authors.initials: Y
authors.lastname: Le Corre
authors.forename: E
authors.initials: E
authors.lastname: Vessières
authors.forename: L
authors.initials: L
authors.lastname: Grimaud
authors.forename: B
authors.initials: B
authors.lastname: Toutain
authors.forename: C
authors.initials: C
authors.lastname: Labat
authors.forename: Y
authors.initials: Y
authors.lastname: Mauras
authors.forename: T G
authors.initials: TG
authors.lastname: Gorgels
authors.forename: A A
authors.initials: AA
authors.lastname: Bergen
authors.forename: O
authors.initials: O
authors.lastname: Le Saux
authors.forename: P
authors.initials: P
authors.lastname: Lacolley
authors.forename: G
authors.initials: G
authors.lastname: Lefthériotis
authors.forename: D
authors.initials: D
authors.lastname: Henrion
authors.forename: L
authors.initials: L
authors.lastname: Martin
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D062186:Arterial Pressure; D001158:Arteries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D054338:Cell Transdifferentiation; D020219:Chondrogenesis; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010012:Osteogenesis; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D011561:Pseudoxanthoma Elasticum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D012039:Regional Blood Flow; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059289:Vascular Stiffness; D014661:Vasoconstriction
chemical_list: D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D002118:Calcium; D024043:Collagen Type II; D050659:Core Binding Factor Alpha 1 Subunit; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D053495:Osteopontin; D012333:RNA, Messenger; D055748:SOXB1 Transcription Factors; C504743:Abcc6 protein, mouse; C493716:Runx2 protein, mouse; C527783:Sox2 protein, mouse; C506896:Spp1 protein, mouse
keywords: ABC transporters; arteriosclerosis; calcification, physiologic