A Role for the β-Catenin/T-Cell Factor Signaling Cascade in Vascular Remodeling

Abstract

Abstract-␤-Catenin and T cell factor (Tcf) are distal components of the highly conserved Wnt pathway that govern cell fate and proliferation in lower organisms. Thus, we hypothesized that the regulation of ␤-catenin and Tcf played a critical role in vascular remodeling. The first objective was to define ␤-catenin expression in vascular smooth muscle cells (VSMCs) after balloon injury. Indeed, ␤-catenin mRNA and protein were significantly elevated 7 days after balloon injury in the rat carotid artery. We hypothesized that ␤-catenin accumulation in response to vascular injury inhibited VSMC apoptosis. In line with our hypothesis, transfection of a degradation-resistant ␤-catenin transgene into rat VSMCs significantly inhibited apoptosis. Accumulation of ␤-catenin also resulted in a 10-fold increase in the activation of Tcf. To test if Tcf was necessary to confer ␤-catenin-induced survival, loss of function studies were carried out with a dominant negative Tcf-4 transgene lacking the ␤-catenin binding domain, Tcf4 (

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

“…Altogether, this data suggest Wnt3a alters the phenotype of vascular smooth muscle cells. As Wnt signaling is upregulated after vascular injury, 7,14 this data highlight a potential role for Wnt3a in controlling smooth muscle cell phenotype during vascular wound repair and remodeling processes.…”

“…These channels are comprised of subunit proteins encoded by the multigene connexin family, of which connexin 43 is the predominant connexin expressed by vascular smooth muscle cells. 28 It has previously been reported that connexin 43 expression is upregulated in smooth muscle cells in response to injury in rodent models and in early human atherosclerosis, situations in which elevated Wnt signaling has been reported 7,14 and in which increased extracellular matrix synthesis is well documented. 3,38 Reducing connexin 43 expression has been shown to inhibit lesion development in rodent models of atherosclerosis and acute vascular injury, [39][40][41] suggesting potential pro-atherogenic functions for gap junction communication.…”

“…5,6 Growing evidence suggest a role for the Wnt family of secreted glycoproteins and their associated signaling pathways in regulating many of the processes involved in vascular wound repair and remodeling events. [7][8][9][10][11][12][13][14] However, the precise mechanisms and outcomes of Wnt signaling in such settings remain unclear. Moreover, the effect of specific Wnt family members on vascular cell phenotype remain undefined.…”

Atherosclerotic Calcification: Wnt Is the Hint

“…Interestingly, Wnt signaling in ECs has been shown to activate proinflammatory gene expression via inhibition of canonical Wnt signaling and activation of the noncanonical Ca 2+ ‐dependent pathway via ligand Wnt5a 88, 89. Several studies have demonstrated a direct link between canonical Wnt signaling via ligands Wnt1, Wnt2, and Wnt3a and arterial smooth muscle cell proliferation, which underlies the intimal thickening stage of atherosclerosis 20, 21, 90, 91. Canonical Wnt signaling and LRP5 have also been directly implicated in the promotion of foam cell formation 6.…”

TCF7L2 single nucleotide polymorphisms, cardiovascular disease and all-cause mortality: the Atherosclerosis Risk in Communities (ARIC) study

“…Interestingly, a specific role for TCF-4 has been shown in the process of vascular remodelling. Moreover, transcriptional activation of TCF-4 turns on the nuclear factor-.B signalling pathway, which regulates inflammatory signalling pathways [5]. Data from the MONICA/KORA Surveys showed that the T allelemodel assessment of per cent beta cell function and fasting insulin, suggesting a role in pancreatic beta cell function [3].…”