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The Interplay of Wnt‐ and PPARγ‐signaling in macrophages & vascular smooth muscle cells during vascular calcification

Molecular mechanisms and structural changes of the vessel wall including inflammation and vascular calcification (VC) are linked to atherosclerosis, and various cell types such as macrophages and vascular smooth muscle cells (VSMC) are involved. Importantly, VC enhances the risk of acute cardiovascular events by 4‐fold. Hence, it is of great importance to reveal underlying molecular mechanisms to prevent this outcome. The environmental shifts in atherosclerotic plaques stimulate the expression of Wnt5a and BMP‐2. Both factors are secreted by M1‐macrophages and induce an osteo‐chondrogenic phenotype of VSMC by enhancing SOX9 and RUNX2 mRNA expression while modulating the Wnt‐signaling pathway. Subsequently, we observed a 2‐fold upregulation of Wnt5a expression in human macrophages treated with serum from patients with acute myocardial infarction. However, PPARγ‐signaling drives the secretion of Wnt‐inhibitors (Dkk1, sFRPs) in multiple cell types. This raises the question if PPARγ‐stimulation can limit the deleterious effects of pathologically activated Wnt‐signaling in VC by attenuating the osteogenic differentiation of VSMC. Thus, identification of the molecular pathways linking PPARγ‐and Wnt‐signaling may be of major clinical importance for the treatment of VC. Additionally, the existence of already registered PPARγ‐agonists could receive new clinical indications.