Figure 6.

Wnt3a and Wnt5a signalling via divergent pathways to promote VSMC survival, and these pathways are differentially affected by aging. (a) In VSMCs from young mice, Wnt3a, in the presence of H₂O₂, activated β‐catenin/TCF‐mediated transcription and upregulation of the survival genes IGF‐1, WISP‐1 and WISP‐2. However, only WISP‐2 was necessary for rescue of H₂O₂‐induced VSMC apoptosis. Conversely, Wnt5a, in the presence of H₂O₂, induced β‐catenin nuclear translocation, but not β‐catenin/TCF activation. Instead, Wnt5a‐mediated rescue of VSMCs was dependent on CREB activation and CREB‐dependent WISP‐1 upregulation (Mill et al., 2014). Overall in young VSMCs, both Wnt pathways contribute to VSMC survival, which in atherosclerosis would promote fibrous cap maintenance and plaque stability. (b) In VSMCs from old mice, Wnt3a rescued H₂O₂‐induced apoptosis, whereas the ability of Wnt5a to phosphorylate CREB was impaired resulting in a lack of CREB‐dependent WISP‐1 upregulation and cell survival. Thus, in aged VSMCs, only one of the two Wnt pathways investigated here promotes VSMC survival. In atherosclerosis, this could impair fibrous cap maintenance predisposing fibrous cap thinning and plaque instability