血管内皮生长因子受体-2 抑制促进了卒中新生啮齿动物模型中的细胞死亡和内皮细胞增殖的限制。
Vascular endothelial growth factor receptor-2 inhibition promotes cell death and limits endothelial cell proliferation in a neonatal rodent model of stroke.
机构信息
Department of Pediatrics, University of California, San Francisco, San Francisco Calif 94143-0663, USA.
出版信息
Stroke. 2010 Feb;41(2):343-9. doi: 10.1161/STROKEAHA.109.564229.
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.
背景与目的
最近在新生啮齿动物中风模型中的研究表明，恢复部分归因于缺氧诱导因子-1-a 及其下游靶标血管内皮生长因子的上调。血管内皮生长因子在缺氧损伤后上调，并参与神经元存活、血管生成和神经发生在恢复过程中。
方法
我们在 10 天大的大鼠中进行了 1.5 小时的短暂性大脑中动脉闭塞，在闭塞期间通过弥散加权 MRI 验证损伤，以确定血管内皮生长因子受体-2（VEGFR2）抑制对损伤、细胞凋亡和血管生成的影响。再灌注后 2 天，幼鼠接受 VEGFR 抑制剂 SU5416（10mg/kg 剂量）或载体（1%二甲基亚砜）治疗 3 天。
结果
与载体处理组和单纯损伤组相比，VEGFR2 抑制在损伤后 7 天加重了损伤（P<0.01）。此外，受体抑制与损伤后 5 天 VEGFR2 表达增加（P<0.05）和血影蛋白裂解增加有关，有利于钙蛋白酶介导的、半胱天冬酶-3 非依赖性裂解（P<0.01）。在治疗组中，在 7 天看到的 cleaved caspase-3 染色面积增加（P<0.01）在这个时间点上，胶质纤维酸性蛋白和 Iba-1 表达的胶质增生或巨噬细胞募集没有差异。最后，VEGFR2 抑制并不影响总体血管表面积，但减少损伤尾状核内皮细胞增殖。
结论
VEGFR2 信号通路的抑制会加重新生卒中后的损伤、影响细胞死亡并减少内皮细胞增殖。损伤加重可能部分归因于细胞命运从凋亡向坏死的转变，以及对损伤大脑中血管生成的影响。
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