title: The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells.
abstract: Vascular calcification is a hallmark of advanced atherosclerosis. Here we show that deletion of the nuclear receptor PPARγ in vascular smooth muscle cells of low density lipoprotein receptor (LDLr)-deficient mice fed an atherogenic diet high in cholesterol, accelerates vascular calcification with chondrogenic metaplasia within the lesions. Vascular calcification in the absence of PPARγ requires expression of the transmembrane receptor LDLr-related protein-1 in vascular smooth muscle cells. LDLr-related protein-1 promotes a previously unknown Wnt5a-dependent prochondrogenic pathway. We show that PPARγ protects against vascular calcification by inducing the expression of secreted frizzled-related protein-2, which functions as a Wnt5a antagonist. Targeting this signalling pathway may have clinical implications in the context of common complications of atherosclerosis, including coronary artery calcification and valvular sclerosis.
authors.affiliation: CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Woldt
authors.forename: Jérome
authors.initials: J
authors.lastname: Terrand
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mlih
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Matz
authors.forename: Véronique
authors.initials: V
authors.lastname: Bruban
authors.forename: Fanny
authors.initials: F
authors.lastname: Coudane
authors.forename: Sophie
authors.initials: S
authors.lastname: Foppolo
authors.forename: Zeina
authors.initials: Z
authors.lastname: El Asmar
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Chollet
authors.forename: Ewa
authors.initials: E
authors.lastname: Ninio
authors.forename: Audrey
authors.initials: A
authors.lastname: Bednarczyk
authors.forename: Danièle
authors.initials: D
authors.lastname: Thiersé
authors.forename: Christine
authors.initials: C
authors.lastname: Schaeffer
authors.forename: Alain
authors.initials: A
authors.lastname: Van Dorsselaer
authors.forename: Christian
authors.initials: C
authors.lastname: Boudier
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Philippe
authors.initials: P
authors.lastname: Boucher
mesh_terms: D000818:Animals; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins; D047495:PPAR gamma; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C438615:Wnt5a protein, mouse