C. Miele et al., Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways, J BIOL CHEM, 275(28), 2000, pp. 21695-21702
In this study we have investigated the molecular mechanisms of insulin and
insulin-like growth factor-I (IGF-I) action on vascular endothelial growth
factor (VEGF) gene expression. Treatment with insulin or IGF-I for 4 h incr
eased the abundance of VEGF mRNA in NIH3T3 fibroblasts expressing either th
e human insulin receptor (NIH-IR) or the human IGF-I receptor (NIH-IGFR) by
6- and 8-fold, respectively. The same elevated levels of mRNA were maintai
ned after 24 h of stimulation with insulin, whereas IGF-I treatment further
increased VEGF mRNA expression to 12-fold after 24 h. Pre-incubation with
the phosphatidylinositol 3-kinase inhibitor wortmannin abolished the effect
of insulin on VEGF mRNA expression in NIH-IR cells but did not modify the
IGF-I-induced VEGF mRNA expression in NIH-IGFR cells. Blocking mitogen-acti
vated protein kinase activation with the MEK inhibitor PD98059 abolished th
e effect of IGF-I on VEGF mRNA expression in NIH-IGFR cells but had no effe
ct on insulin-induced VEGF mRNA expression in NIH-IR cells. Expression of a
constitutively active PKB in NIH-IR cells induced the expression of VEGF m
RNA, which was not further modified by insulin treatment. We conclude that
VEGF induction by insulin and IGF-I occurs via different signaling pathways
, the former involving phosphatidylinositol 3-kinase/protein kinase B and t
he latter involving MEK/mitogen-activated protein kinase.