Abstract
Vascular calcification (VC), the ectopic deposition of calcium phosphate crystals in the vessel wall, is one of the primary contributors to cardiovascular death. The pathology of VC is determined by vascular topography, pre-existing diseases, and our genetic heritage. VC evolves from inflammation, mediated by macrophages, and from the osteochondrogenic transition of vascular smooth muscle cells (VSMC) in the atherosclerotic plaque. This pathologic transition partly resembles endochondral ossification, involving the chronologically ordered activation of the β-catenin-independent and -dependent Wingless and Int-1 (WNT) pathways and the termination of peroxisome proliferator-activated receptor γ (PPARγ) signal transduction. Several atherosclerotic plaque studies confirmed the differential activity of PPARγ and the WNT signaling pathways in VC. Notably, the actively regulated β-catenin-dependent and -independent WNT signals increase the osteochondrogenic transformation of VSMC through the up-regulation of the osteochondrogenic transcription factors SRY-box transcription factor 9 (SOX9) and runt-related transcription factor 2 (RUNX2). In addition, we have reported studies showing that WNT signaling pathways may be antagonized by PPARγ activation via the expression of different families of WNT inhibitors and through its direct interaction with β-catenin. In this review, we summarize the existing knowledge on WNT and PPARγ signaling and their interplay during the osteochondrogenic differentiation of VSMC in VC. Finally, we discuss knowledge gaps on this interplay and its possible clinical impact.
Highlights
Cardiovascular disease (CVD) affects more than 420 million people worldwide, causing 18 million deaths annually
Beyond the local impact of secreted frizzled-related protein (sFRP) mediated via peroxisome proliferator-activated receptor γ (PPARγ) activation on vascular smooth muscle cells (VSMC), a recent study has evidenced the ability of sFRP5 to directly interact with lipoprotein receptor 1 (LRP1) in macrophages in pro-inflammatory conditions
Thereby, it induces its proteasomal degradation, as suggested by the authors [157]. This may result in increased availability of WNT5a originating from macrophages, which might promote the osteochondrogenic transition of VSMC in the atherosclerotic plaque
Summary
Cardiovascular disease (CVD) affects more than 420 million people worldwide, causing 18 million deaths annually. The plaque may narrow the affected artery, which induces ischemia in the supplied organs This narrowing results in CVDs such as CHD, peripheral artery disease, as well as acute vascular events like myocardial infarction and stroke. Athletes with a high physical activity display a higher prevalence of CAC than sedentary people, while still having a lower incidence of CVD and longer life expectancy [9]. These varying effects of CAC in different population groups indicate that a change in diet and physical exercise may positively change the impact of VC. The respective roles of Wingless/Int-1 (WNT)- and Peroxisome proliferator-activated receptor γ (PPARγ) signaling in atherosclerosis and VC will be explained before discussing existing knowledge about their interplay as well as its relevance for VC
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