Abstract 19224: Loss of LRP6/TCF7L2 Regulation of Vascular Smooth Muscle Cell Phenotype Contributes to Coronary Artery Disease
Loss of function mutations in the Wnt co-receptor Low Density Lipoprotein Receptor Related Protein 6 (LRP6) cause early coronary artery disease (CAD) in humans. Using in vivo model of a highly penetrant LRP6 mutation (LRP6R611C), we show that loss of LRP6 function significantly alters VSMC phenotype resulting in reduced contractile protein expression and increased expression of markers of stemness. These changes are associated with increased expression of growth factors and activation of their downstream signaling. Loss of VSMC differentiation in LRP6R611C mice accelerated neointima formation upon carotid artery guide wire injury, led to neointima formation in aortic root and coronary artery on high cholesterol diet and augmented atherosclerosis burden in LDLR-/- mice, as compared to LDLR-/- mice. A common feature of growth factors PDGF-AA, -BB, IGF1, and stemness markers vimentin and c-kit, which were found to be expressed at much greater levels in LRP6R611C vs. WT VSMCs is their regulation by transcription factor SP1. LRP6R611C VSMC exhibited increased expression of SP1 protein and mRNA. Wnt3a treatment in vitro significantly reduced SP1 and its target proteins. Further mechanistic studies identified Wnt signaling transcription factor TCF7l2 as an important regulator of SP1. Restoration of TCFL2 levels by i.p. administration of Wnt3a led to decreased neointima formation in LRP6R611C mice by SP1-dependent reduction of growth factors, vimentin and c-kit, and subsequent increase in expression of VSMC contractile proteins. In conclusion, our studies establish the role of LRP6/TCF7L2 in regulation of vascular integrity and demonstrate that defects caused by impaired Wnt signaling can be reversed by restoring its function.
Author Disclosures: R. Srivastava: None. G. Go: None. J. Zhang: None. A. Mani: None.
- © 2014 by American Heart Association, Inc.