期刊
STROKE
卷 41, 期 2, 页码 343-349出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.109.564229
关键词
angiogenesis; apoptosis; cerebral ischemia; development; necrosis; postnatal
资金
- National Institutes of Health [NS35902]
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. (Stroke. 2010; 41: 343-349.)
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