DEVELOPMENT Dueling Pathways in Vascular Development

The cells that make up arteries and veins are derived from angioblasts, which give rise to arterial and venous progenitors that migrate and coalesce to form the vasculature. In zebrafish, mutation of the gridlock gene, which encodes a transcriptional repressor, leads to insufficient production of arterial cells and disruption of vascular development. The small molecule GS4012 suppresses the vascular abnormalities caused by gridlock mutation, which has been attributed to stimulation of vascular endothelial growth factor (VEGF) signaling. In a screen for small molecule suppressors of the gridlock phenotype, Hong et al. identified GS4898, which is structurally distinct from GS4012 but resembles several inhibitors of protein kinases. The VEGF signaling pathway involves activation of phosphatidylinositol 3-kinase (PI3K), and GS4898 inhibited activation of Akt, which is downstream of PI3K. Moreover, two known inhibitors of PI3K, LY294002 and wortmannin, also suppressed the gridlock phenotype. This seemed paradoxical, given that GS4898 is believed to function by stimulating VEGF signaling, leading the authors to postulate that the branch of the VEGF pathway involving PI3K inhibits a limb mediated through phospholipase C- (PLC-) and extracellular signal-regulated kinase (ERK), with the latter promoting arterial specification. Immunostaining revealed that, during vasculogenesis, phosphorylated ERK was preferentially localized in arterial progenitors and newly differentiated arterial endothelial cells. Further pharmacological analysis and experiments with constitutively active or dominant-negative Akt mutants all supported the notion that the two branches of the VEGF signaling pathway acted in opposing directions, with activation of the ERK branch promoting arterial specification and activation of the PI3K branch promoting venous specification.

C. C. Hong, Q. P. Peterson, J.-Y. Hong, R. T. Peterson, Artery/vein specification is governed by opposing phosphatidylinositol-3 kinase and MAP kinase/ERK signaling. Curr. Biol. 16, 1366-1372 (2006). [PubMed]