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Cardiometabolic diseases increasingly afflict our aging, dysmetabolic population. Complex signals regulating low-density lipoprotein receptor-related protein (LRP) and frizzled protein family members – the plasma membrane receptors for the cadre of Wnt polypeptide morphogens – contribute to the control of cardiovascular homeostasis.Both canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) Wnt signaling programs control vascular smooth muscle (VSM) cell phenotypic modulation in cardiometabolic disease. LRP6 limits VSM proliferation, reduces arteriosclerotic transcriptional reprogramming, and preserves insulin sensitivity while LRP5 restrains foam cell formation. Adipose, skeletal muscle, macrophages, and VSM have emerged as important sources of circulating Wnt ligands that are dynamically regulated during the prediabetes−diabetes transition with cardiometabolic consequences. Platelets release Dkk1, a LRP5/LRP6 inhibitor that induces endothelial inflammation and the prosclerotic endothelial−mesenchymal transition. By contrast, inhibitory secreted frizzled-related proteins shape the Wnt signaling milieu to limit myocardial inflammation with ischemia-reperfusion injury. VSM sclerostin, an inhibitor of canonical Wnt signaling in bone, restrains remodeling that predisposes to aneurysm formation, and is downregulated in aneurysmal vessels by epigenetic methylation.Components of the Wnt signaling cascade represent novel targets for pharmacological intervention in cardiometabolic disease. Conversely, strategies targeting the Wnt signaling cascade for other therapeutic purposes will have cardiovascular consequences that must be delineated to establish clinically useful pharmacokinetic–pharmacodynamic relationships.