The nuclear hormone receptor PPARγ counteractsvascular calcification by inhibiting Wnt5a signallingin vascular smooth muscle cells

摘要

Vascular calcification is a hallmark of advanced atherosclerosis. Here we show that deletionof the nuclear receptor PPARγ in vascular smooth muscle cells of low density lipoproteinreceptor (LDLr)-deficient mice fed an atherogenic diet high in cholesterol, accelerates vascularcalcification with chondrogenic metaplasia within the lesions. Vascular calcification in theabsence of PPARγ requires expression of the transmembrane receptor LDLr-related protein-1 in vascular smooth muscle cells. LDLr-related protein-1 promotes a previously unknownWnt5a-dependent prochondrogenic pathway. We show that PPARγ protects against vascularcalcification by inducing the expression of secreted frizzled-related protein-2, which functionsas a Wnt5a antagonist. Targeting this signalling pathway may have clinical implications in thecontext of common complications of atherosclerosis, including coronary artery calcificationand valvular sclerosis.