The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells

• Published in: Nature communications 2012, Vol.3 (1), p.1077-1077, Article 1077
• Main Authors: Woldt, Estelle, Terrand, Jérome, Mlih, Mohamed, Matz, Rachel L., Bruban, Véronique, Coudane, Fanny, Foppolo, Sophie, El Asmar, Zeina, Chollet, Maria Eugenia, Ninio, Ewa, Bednarczyk, Audrey, Thiersé, Danièle, Schaeffer, Christine, Van Dorsselaer, Alain, Boudier, Christian, Wahli, Walter, Chambon, Pierre, Metzger, Daniel, Herz, Joachim, Boucher, Philippe
• Format: Article
• Language: English
• Subjects: 631/80/86/2363; 692/698/1671/1668; 692/699/75/593/2193; Animals; Biochemistry, Molecular Biology; Cellular Biology; Humanities and Social Sciences; Humans; Immunoblotting; Immunoprecipitation; In Situ Hybridization; In Vitro Techniques; Life Sciences; Low Density Lipoprotein Receptor-Related Protein-1 - genetics; Low Density Lipoprotein Receptor-Related Protein-1 - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Models, Biological; multidisciplinary; Muscle, Smooth, Vascular - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; PPAR gamma - agonists; PPAR gamma - genetics; PPAR gamma - metabolism; Science; Science (multidisciplinary); Thiazolidinediones - pharmacology; Vascular Calcification - genetics; Vascular Calcification - metabolism; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt-5a Protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2087

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. Vascular calcification is commonly associated with advanced stages of atherosclerosis. Woldt et al . show that the nuclear hormone receptor PPARγ in vascular smooth muscle cells protects mice from vascular calcification by inhibiting Wnt5a signalling triggered by activation of the cell-surface receptor LRP1.