Activation of MAP kinase (ERK-1/ERK-2), tyrosine kinase and VEGF in the human brain following acute ischaemic stroke
We examined expression of vascular endothelial growth factor (VEGF), together with phosphorylation of mitogen activated protein kinase (MAP) kinase (ERK1 and ERK2) and tyrosine phosphorylation in post-mortem material taken from 19 patients and in serum taken serially from 29 patients after acute ischaemic stroke. Expression of VEGF was significantly increased in the majority of patients following acute stroke at all of the time points, compared to normal controls. Highest expression occurred at day 7 (value 588± 688 ng/ml; p=0.005), and it remained elevated at 14 days after stroke. Expression of VEGF correlated with infarct volume, clinical disability (SSS) and peripheral leukocytosis, and was significantly higher in patients with atherothrombotic large vessel disease and ischaemic heart disease (p<0.05 in all cases). In the grey matter penumbra, 13 out of 19 patients showed an increase in MAP kinase tyrosine phosphorylation. In almost all cases, ERK-2 phosphorylation was higher than ERK1. Of these 13 patients, 11 also showed a general increase in tyrosine kinase phosphorylation, whilst 8 expressed increased levels of VEGF protein. In tissue examined directly from the infarct core, activation of the above proteins was not observed in the majority of patients. There was no relationship between activation of MAP kinase and expression of VEGF. We also examined expression of phosphorylated MAP kinase by immunohistochemistry, and found increased immunoreactivity in neurones, astroglial cells, reactive microglia and endothelial cells in areas surrounding infarcts, especially in areas with the highest density of microvessels. In conclusion, chronic activation of tyrosine phosphorylated events, in particular MAP kinase (ERK1/ERK2) occurs consistently in the grey matter penumbra of brain tissue following ischaemic stroke, and may be associated with increase in expression of VEGF. These signal transduction events could be important determinants of the extent of neuronal survival and/or angiogenic activity in the recovering brain tissue.