| 20101028 |
Shimotake J, Derugin N, Wendland M, Vexler ZS, Ferriero DM: Vascular endothelial growth factor receptor-2 inhibition promotes cell death and limits endothelial cell proliferation in a neonatal rodent model of stroke. Stroke. 2010 Feb;41(2):343-9.
BACKGROUND AND PURPOSE: Recent studies in neonatal rodent stroke models suggest that recovery is due in part to upregulation of hypoxia-inducible factor-1-a and its downstream target, vascular endothelial growth factor. Vascular endothelial growth factor is upregulated after a hypoxic insult and is involved in neuronal survival, angiogenesis, and neurogenesis during the recovery process. METHODS: We performed a 1.5-hour transient middle cerebral artery occlusion in 10-day-old rats with injury verified by diffusion-weighted MRI during occlusion to determine the effects of vascular endothelial growth factor receptor-2 (VEGFR2) inhibition on injury, apoptosis, and angiogenesis. Two days after reperfusion, the pups received either the VEGFR inhibitor, SU5416 (10 mg/kg per dose) or vehicle (1% dimethyl sulfoxide) for 3 days. RESULTS: VEGFR2 inhibition worsened injury 7 days after injury when compared with the vehicle-treated and injury-alone groups (P <0.01). Furthermore, receptor inhibition was associated with increased VEGFR2 expression 5 days after injury (P <0.05) and increased spectrin cleavage with a shift in favor of the calpain-mediated, caspase-3-independent cleavage (P <0.01). Increased areas of cleaved caspase-3 staining were seen in treated rats at 7 days (P <0.01) There were no differences in gliosis or macrophage recruitment as measured by glial fibrillary acidic protein and Iba-1 expression at this time point. Lastly, VEGFR2 inhibition did not affect the overall vessel surface area but reduced endothelial cell proliferation in injured caudate. CONCLUSIONS: Inhibition of VEGFR2 signaling worsens injury, affects cell death, and reduces endothelial cell proliferation after neonatal stroke. Injury exacerbation may be in part due to a shift of cell fate from apoptosis to necrosis on the continuum spectrum of cell death as well as effects on angiogenesis in the injured brain. |
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