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 LRP6(R611C) 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. LRP6(R611C) 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 LRP6(R611C) 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.
Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Roshni
R
Srivastava
Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Jiasheng
J
Zhang
Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Gwang-Woong
GW
Go
Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Anand
A
Narayanan
Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Timothy P
TP
Nottoli
Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: arya.mani@yale.edu.
Arya
A
Mani
D000818:Animals; D000066670:Cell Plasticity / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism*; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*
D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein