Glycogen synthase kinase 3 beta (Gsk3b) acts as a negative modulator in endothelial cells through the Wnt/β-catenin/PI3K/AKT/Gsk3b axis in cancer-induced angiogenesis. However, the function of Gsk3b during embryonic angiogenesis remains unclear. Here, either gsk3b knockdown by morpholino or Gsk3b loss of activity by LiCl treatment had serious phenotypic consequences, such as defects in the positioning and patterning of intersegmental blood vessels and reduction of vegfaa121 and vegfaa165 transcripts. In embryos treated with the phosphatidylinositol 3-kinase inhibitor, angiogenesis was severely inhibited, along with reduced Wnt, phosphorylated AKT and phosphorylated Gsk3b, suggesting that the remaining Gsk3b in somites could still degrade β-catenin, resulting in decreased vascular endothelial growth factor Aa(VegfAa) expression. However, in gsk3b-mRNA-overexpressed embryos, intersegmental vessels ectopically sprouted by the increase in phosphorylated-Gsk3b which prevented the degradation of β-catenin and promoted the increase in phosphorylated AKT activity, thus increasing VegfAa expression in somites. Interestingly, the Gsk3b-dependent cross-talk between PI3K/AKT and Wnt/β-catenin suggests that Wnt/β-catenin and PI3K/AKT interaction controls embryonic angiogenesis by a positive feedback loop rather than a hierarchical framework such as that found in cancer-induced angiogenesis. Thus, both active and inactive forms of Gsk3b mediate the cooperative signaling between Wnt/β-catenin and PI3K/AKT to control VegfAa expression in somites during angiogenesis in zebrafish embryos.
Keywords: Gsk3b; angiogenesis; somite; vascular endothelial growth factor; zebrafish.
© 2014 FEBS.