Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease

Mutations in Wnt-signaling coreceptor LRP6 have been linked to coronary artery disease (CAD) by unknown mechanisms. Here, we show that reduced LRP6 activity in LRP6R611C mice promotes loss of vascular smooth muscle cell (VSMC) differentiation, leading to aortic medial hyperplasia. Carotid injury augmented these effects and led to partial to total vascular obstruction. LRP6R611C mice on high-fat diet displayed dramatic obstructive CAD and exhibited an accelerated atherosclerotic burden on LDLR knockout background. Mechanistically, impaired LRP6 activity leads to enhanced non-canonical Wnt signaling, culminating in diminished TCF7L2 and increased Sp1-dependent activation of PDGF signaling. Wnt3a administration to LRP6R611C mice improved LRP6 activity, led to TCF7L2-dependent VSMC differentiation, and rescued post-carotid-injury neointima formation. These findings demonstrate the critical role of intact Wnt signaling in the vessel wall, establish a causal link between impaired LRP6/TCF7L2 activities and arterial disease, and identify Wnt signaling as a therapeutic target against CAD. [Display omitted] •LRP6R611C mice exhibit aortic medial hyperplasia and coronary artery disease•LRP6R611C mice VSMCs have reduced TCF7L2 expression and are undifferentiated•Activation of non-canonical Wnt is increased in LRP6R611C mice VSMCs•Wnt3a normalizes the non-canonical Wnt and TCF7L2 activities and rescues the phenotype Srivastava et al. demonstrate that loss of LRP6 activity results in loss of vascular smooth muscle cell (VSMC) differentiation, neointima formation, and coronary artery disease (CAD) via reduced TCF7L2-dependent inhibition of Sp1. In vivo, Wnt3a activates LRP6 and rescues TCF7L2 expression and the vascular phenotype, signifying the important role of the Wnt/LRP6/TCF7L2 in maintaining vascular integrity.