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

Estelle Woldt, Jérome Terrand, Mohamed Mlih, Rachel L. Matz, Véronique Bruban, Fanny Coudane, Sophie Foppolo, Zeina El Asmar, Maria Eugenia Chollet, Ewa Ninio, Audrey Bednarczyk, Danièle Thiersé, Christine Schaeffer, Alain Van Dorsselaer, Christian Boudier, Walter Wahli, Pierre Chambon, Daniel Metzger, Joachim Herz, Philippe Boucher

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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.

Original languageEnglish (US)
Article number1077
JournalNature communications
Volume3
DOIs
StatePublished - Oct 8 2012

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Woldt, E., Terrand, J., Mlih, M., Matz, R. L., Bruban, V., Coudane, F., Foppolo, S., El Asmar, Z., Chollet, M. E., Ninio, E., Bednarczyk, A., Thiersé, D., Schaeffer, C., Van Dorsselaer, A., Boudier, C., Wahli, W., Chambon, P., Metzger, D., Herz, J., & Boucher, P. (2012). The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells. Nature communications, 3, [1077]. https://doi.org/10.1038/ncomms2087