Our studies observed that, consistent with the literature, ischemic/hypoxic insults increased the expression of
voltage-gated potassium channel (Kv) 1.2
potassium channel as well as elevating the endogenous level of
vascular endothelial growth factor (
VEGF) in neurons of adult rat brain following
middle cerebral artery occlusion and in SH-SY5Y cells after
hypoxia and
glucose deprivation. Concomitantly, we also observed that ischemic injury increased the
tyrosine phosphorylation of Kv 1.2 in in vivo and in vitro; the introduction of exogenous
VEGF could attenuate cell death in in vitro models. Furthermore, we found that the protective effect of
VEGF is mediated through its up-regulative actions on the
tyrosine phosphorylation of Kv 1.2, which in turn has a direct influence on cell viability after ischemic insult. In substantiation of this result, we used anti-sense methodology to suppress the expression of endogenous
VEGF, which significantly inhibited the
tyrosine phosphorylation of Kv 1.2 and increased cell death elicited by ischemic/hypoxic injury. Finally, the enhancement of the
tyrosine phosphorylation of the channel by
VEGF in neuronal cells was significantly attenuated in the presence of
wortmannin, an inhibitor of
phosphatidylinositol 3-kinase (PI3-K), or genestin, an inhibitor of
tyrosine kinase, thus suggesting that the phosphorylation of Kv 1.2 induced by
VEGF is mechanistically linked to the PI3-K pathway.