电针对脑缺血再灌注大鼠脑内血管新生影响的研究
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摘要
目的缺血性脑血管病遗留的神经功能障碍一直是困扰人类医学的难题。随着对缺血性脑血管病研究的深入,发现脑缺血后相当部分的血管能自然再通或溶栓治疗后血流恢复再通,但随之出现再灌注损伤。治疗性血管新生方法的出现,为缺血性脑血管病的治疗开辟了一条通向缺血性脑血管病血管再生的新途径。研究发现,适当地调控治疗性血管生成的进程对有效的改善脑缺血很有必要。血管新生的调节途径主要包括两条:一条是血管内皮生长因子(vascular endothelialgrowth factor,VEGF)及其受体(flt-1等)调节通路,另一条是血管生成素(angiopoietin,Ang)及其受体(Tie)调节通路,这两条途径协同作用,共同促进机体血管形成。血管内皮生长因子是已知的促进血管生长作用最强的细胞因子,VEGF/VEGFR系统激活使内皮细胞增生并诱导新生血管形成,新生血管从正常脑组织向半暗带及缺血中心区延伸,增加受累脑组织再灌注及供氧量,从而减轻缺血再灌注损伤。Ang-1/Tie-2调节通路对于血管生成过程中血管的成熟与稳定、调控血管的完整性有重要意义。血管生成素-1(Ang-1)可以抑制血管内皮细胞的凋亡,减轻脑缺血后血脑屏障的渗漏从而减小梗死体积,促进血管内皮细胞的出芽与迁徙。本课题选用大脑中动脉栓塞制备脑缺血再灌注模型,观察电针对VEGFmRNA、Ang-1mRNA/Tie-2和对脑内血管新生的影响,探讨电针抗脑缺血再灌注损伤的可能机制。方法采用SD大鼠随机分为模型组(按缺血再灌注1d、2d、4d和8d分4个亚组)、电针组(按缺血再灌注1d、2d、4d和8d分别加电针刺激分为4个亚组)、假手术组、正常对照组,每组10只,共100只。采用改进的Longa线栓法,制备大脑中动脉线栓法脑缺血再灌注模型。并采用Zea-Longa5级评分标准对模型大鼠神经功能障碍评分,只有神经功能障碍在1级以上的大鼠才能保留下来。电针组选用疏密波刺激“百会”、“水沟”、双侧“足三里”穴。运用免疫组化法检测各组大鼠右侧大脑皮层的CD34阳性微血管密度和Tie-2表达的变化;运用原位杂交法检测各组大鼠右侧大脑皮层中的VEGFmRNA和Ang-1mRNA表达水平;并对各指标的时程变化和电针干预的影响进行分析。所有数据均输入计算机,以SPSS11.0软件统计包处理。
结果(1)模型组和电针组大鼠造模后出现不同程度的神经功能缺损,脑缺血再灌注后各时点上,电针组各亚组神经功能缺损评分明显低于模型组相应亚组的评分(P<0.05),表明电针可以减轻脑缺血再灌注后的神经功能缺损;(2)模型组和电针组各亚组大鼠缺血侧大脑皮层均可见微血管增生,各时相电针组微血管密度高于模型组(P<0.05),说明电针能促进脑缺血再灌注后的血管新生;(3)模型组和电针组各亚组大鼠缺血侧大脑皮层VEGFmRNA表达水平升高,与正常组和假手术组比较有明显差异(P<0.05),电针组各亚组大鼠缺血侧大脑皮层VEGFmRNA表达水平明显高于相应时相的模型组亚组,两组相同时相亚组间比较有显著性差异(P<0.05),说明电针能上调脑缺血再灌注后大脑皮层的VEGFmRNA表达水平。(4)模型组和电针组缺血再灌注2d、4d、8d亚组大鼠缺血侧大脑皮层Ang-1mRNA和Tie-2表达水平升高,与正常组和假手术组比较有明显差异(P<0.05),电针组缺血再灌注2d、4d、8d各亚组大鼠缺血侧大脑皮层Ang-1mRNA和Tie-2表达水平明显高于相应时相的模型组亚组,两组相同时相亚组间比较有显著性差异(P<0.05),说明电针能上调脑缺血再灌注后大脑皮层的Ang-1mRNA和Tie-2表达水平。
结论脑缺血再灌注后出现缺血区血管新生,VEGF和Ang-1/Tie-2参与了脑缺血再灌注损伤后缺血区的血管新生的发生过程。电针对脑缺血再灌注损伤后皮层血管新生有良性调节作用,能促进缺血区的血管新生,减轻脑缺血再灌注后的神经缺损,其作用可能是通过上调VEGFmRNA的表达和上调Ang-1mRNA/Tie-2的表达而实现的。
Introduction
The neurological dysfunction leaved over by ischemic ce rebrovascular disease has been a difficult problems of huma n medicine.With the Profound investigation into cerebral a rterial thrombosis,it could induce the injury of ischemia-reperfusion after bloodstream reviving re-canalization.The therapeutic angiogenesis established a new channel to angi ogenesis of ischemia cerebral vascular disease.
Therefore,it is necessary to properly control the proc ess of therapeutic angiogenesis which is effective to impro ve cerebral ischemia.The process of angiogenesis mainly in clude two regulated channels:one is the vascular endotheli al growth factor(VEGF) and its receptor(flt-1,etc.) regu late access,and the other is angiopoietin-1(angiopoietin, Ang) and its receptor(Tie) regulating access,the two chan nels work together to promote angiogenesis.Vascular endoth elial growth factor is a kind of cytokines to promote angio genesis best as we know.The activation of VEGF-VEGFR syste m is to cause hyperplasia endothelial cells and to induce n eovascularization.The new vessels,extending from normal b rain tissue to ischemic region,augment reperfusion and ven tilation of brain tissue to be involved in and lessen ische mia-reperfusion injury.The Ang-1/Tie-2 regulation pathway has significant meaning for the maturity and stability of b lood vessel in the process of angiogenesis.Angiopoietin-1 (Ang-1) could inhibit vascular endothelial cell apoptosis, reducing the Leakage of blood-brain barrier after cerebral ischemia in order to reduce the infarct brain volume,and p romote the budding of vascular endothelial cells.Used the MCAO model,this research approached the mechanism of early acupuncture treating resisting cerebral ischemia-reperfusio n injury and based on the observation of the changes of the VEGFmRNA、Ang-1mRNA/Tie-2 and angiogenesis.
Meterials and Methods
SD rats were randomly divided into the normal control g roup,sham operation group,model group(ischemia-reperfusio n 1day,2days,4days,8days),electro-acupuncture treatment group(ischemia-reperfusion 1day,2days,4days,8days and ad d electro-acupuncture treatment).We used the suture in MCA to establish MCAO isehemia-reperfusion model.The remarks of nerve function deficit referring to Lundy remarking stan dards,Only the rats with over one nerve function deficits can be retained.The acupoints of "BAIHUI","SHUIGOU" and "ZUSANLI" were selected,stimulated with nondense and dens e wave for 30 minutes,observed isehemia brain tissue,dete cted the change of the expression of Tie-2 and microvessel density(MVD) in right cerebral cortex by immunohistochemist ry method,observed the expression of Tie-2 ischemia brain tissue,detected the change of the expression of VEGFmRNA a nd Ang-1mRNA in right cerebral cortex by in situ hybridizat ion method,and analyzed the intervention of time change an d the effects of electro-acupuncture among each indicators. All the datum were processed by SPSS11.0 statistics softwa re package and all results were demonstrated by the average and standard deviation.
Results and Discussion
Rats in electro-acupuncture group and model group have varying degrees of nerve function deficit.Rats in each sub -groups of electro-acupuncture group have lower nerve funct ion deficit scores than the corresponding sub-group of mode 1 group.This shows the electro-acupuncture could significa ntly improve the nerve missing sign of the rats with cerebr a1 ischemia reperfusion.
Rats in each sub-groups of both electro-acupuncture gro up and model group can appear microvascular proliferation i n ipsilateral cerebral cortex tissue,and rats in each phas e of the electro-acupuncture group have higher microvessel density than the model group.This shows electro-acupunctur e could promote angiogenesis after cerebral ischemia-reperf usion.
The expression of VEGFmRNA in ischemic ipsilateral cere bral cortex of both model group rats and electro-acupunctur e group rats were significantly higher than those of normal and sham operation group rats;while the expression of VEG FmRNA in ischemic ipsilateral cerebral cortex of electro-ac upuncture group rats were significantly higher than those o f corresponding phase rats of model group.This shows elect ro-acupuncture can increase the expression level of VEGFmRN A after cerebral ischemia-reperfusion in ipsilateral cerebr al cortex.
The expression of Ang-1mRNA and Tie-2 in ischemic ipsil ateral cerebral cortex after 2,4 or 8 days reperfusion of both model group rats and electro-acupuncture group rats we re significantly higher than those of normal and sham opera tion group rats;while the expression ofAng-1mRNA and Tie-2 in ischemic ipsilateral cerebral cortex of electro-acupunc ture group rats were significantly higher than those of cor responding phase rats of model group.This shows electro-ac upuncture can increase the expression level of Ang-lmRNA an d Tie-2 after cerebral ischemia-reperfusion in ipsilateral cerebral cortex.
Angiogenesis can arise after cerebral ischemia-reperfus ion.VEGF and Ang-1/Tie-2 participate in angiogenesis after cerebral ischemia-reperfusion injury.Electro-acupuncture adjust the process of angiogenesis in brain cortex after ce rebral ischemia-reperfusion injury,can effect urge angioge nesis in ischemia brain tissue and reduce the degree of ner ve function deficit.This could be carried by activating th e expression of VEGFmRNA and Ang-1mRNA/Tie-2.
结果(1)模型组和电针组大鼠造模后出现不同程度的神经功能缺损,脑缺血再灌注后各时点上,电针组各亚组神经功能缺损评分明显低于模型组相应亚组的评分(P<0.05),表明电针可以减轻脑缺血再灌注后的神经功能缺损;(2)模型组和电针组各亚组大鼠缺血侧大脑皮层均可见微血管增生,各时相电针组微血管密度高于模型组(P<0.05),说明电针能促进脑缺血再灌注后的血管新生;(3)模型组和电针组各亚组大鼠缺血侧大脑皮层VEGFmRNA表达水平升高,与正常组和假手术组比较有明显差异(P<0.05),电针组各亚组大鼠缺血侧大脑皮层VEGFmRNA表达水平明显高于相应时相的模型组亚组,两组相同时相亚组间比较有显著性差异(P<0.05),说明电针能上调脑缺血再灌注后大脑皮层的VEGFmRNA表达水平。(4)模型组和电针组缺血再灌注2d、4d、8d亚组大鼠缺血侧大脑皮层Ang-1mRNA和Tie-2表达水平升高,与正常组和假手术组比较有明显差异(P<0.05),电针组缺血再灌注2d、4d、8d各亚组大鼠缺血侧大脑皮层Ang-1mRNA和Tie-2表达水平明显高于相应时相的模型组亚组,两组相同时相亚组间比较有显著性差异(P<0.05),说明电针能上调脑缺血再灌注后大脑皮层的Ang-1mRNA和Tie-2表达水平。
结论脑缺血再灌注后出现缺血区血管新生,VEGF和Ang-1/Tie-2参与了脑缺血再灌注损伤后缺血区的血管新生的发生过程。电针对脑缺血再灌注损伤后皮层血管新生有良性调节作用,能促进缺血区的血管新生,减轻脑缺血再灌注后的神经缺损,其作用可能是通过上调VEGFmRNA的表达和上调Ang-1mRNA/Tie-2的表达而实现的。
Introduction
The neurological dysfunction leaved over by ischemic ce rebrovascular disease has been a difficult problems of huma n medicine.With the Profound investigation into cerebral a rterial thrombosis,it could induce the injury of ischemia-reperfusion after bloodstream reviving re-canalization.The therapeutic angiogenesis established a new channel to angi ogenesis of ischemia cerebral vascular disease.
Therefore,it is necessary to properly control the proc ess of therapeutic angiogenesis which is effective to impro ve cerebral ischemia.The process of angiogenesis mainly in clude two regulated channels:one is the vascular endotheli al growth factor(VEGF) and its receptor(flt-1,etc.) regu late access,and the other is angiopoietin-1(angiopoietin, Ang) and its receptor(Tie) regulating access,the two chan nels work together to promote angiogenesis.Vascular endoth elial growth factor is a kind of cytokines to promote angio genesis best as we know.The activation of VEGF-VEGFR syste m is to cause hyperplasia endothelial cells and to induce n eovascularization.The new vessels,extending from normal b rain tissue to ischemic region,augment reperfusion and ven tilation of brain tissue to be involved in and lessen ische mia-reperfusion injury.The Ang-1/Tie-2 regulation pathway has significant meaning for the maturity and stability of b lood vessel in the process of angiogenesis.Angiopoietin-1 (Ang-1) could inhibit vascular endothelial cell apoptosis, reducing the Leakage of blood-brain barrier after cerebral ischemia in order to reduce the infarct brain volume,and p romote the budding of vascular endothelial cells.Used the MCAO model,this research approached the mechanism of early acupuncture treating resisting cerebral ischemia-reperfusio n injury and based on the observation of the changes of the VEGFmRNA、Ang-1mRNA/Tie-2 and angiogenesis.
Meterials and Methods
SD rats were randomly divided into the normal control g roup,sham operation group,model group(ischemia-reperfusio n 1day,2days,4days,8days),electro-acupuncture treatment group(ischemia-reperfusion 1day,2days,4days,8days and ad d electro-acupuncture treatment).We used the suture in MCA to establish MCAO isehemia-reperfusion model.The remarks of nerve function deficit referring to Lundy remarking stan dards,Only the rats with over one nerve function deficits can be retained.The acupoints of "BAIHUI","SHUIGOU" and "ZUSANLI" were selected,stimulated with nondense and dens e wave for 30 minutes,observed isehemia brain tissue,dete cted the change of the expression of Tie-2 and microvessel density(MVD) in right cerebral cortex by immunohistochemist ry method,observed the expression of Tie-2 ischemia brain tissue,detected the change of the expression of VEGFmRNA a nd Ang-1mRNA in right cerebral cortex by in situ hybridizat ion method,and analyzed the intervention of time change an d the effects of electro-acupuncture among each indicators. All the datum were processed by SPSS11.0 statistics softwa re package and all results were demonstrated by the average and standard deviation.
Results and Discussion
Rats in electro-acupuncture group and model group have varying degrees of nerve function deficit.Rats in each sub -groups of electro-acupuncture group have lower nerve funct ion deficit scores than the corresponding sub-group of mode 1 group.This shows the electro-acupuncture could significa ntly improve the nerve missing sign of the rats with cerebr a1 ischemia reperfusion.
Rats in each sub-groups of both electro-acupuncture gro up and model group can appear microvascular proliferation i n ipsilateral cerebral cortex tissue,and rats in each phas e of the electro-acupuncture group have higher microvessel density than the model group.This shows electro-acupunctur e could promote angiogenesis after cerebral ischemia-reperf usion.
The expression of VEGFmRNA in ischemic ipsilateral cere bral cortex of both model group rats and electro-acupunctur e group rats were significantly higher than those of normal and sham operation group rats;while the expression of VEG FmRNA in ischemic ipsilateral cerebral cortex of electro-ac upuncture group rats were significantly higher than those o f corresponding phase rats of model group.This shows elect ro-acupuncture can increase the expression level of VEGFmRN A after cerebral ischemia-reperfusion in ipsilateral cerebr al cortex.
The expression of Ang-1mRNA and Tie-2 in ischemic ipsil ateral cerebral cortex after 2,4 or 8 days reperfusion of both model group rats and electro-acupuncture group rats we re significantly higher than those of normal and sham opera tion group rats;while the expression ofAng-1mRNA and Tie-2 in ischemic ipsilateral cerebral cortex of electro-acupunc ture group rats were significantly higher than those of cor responding phase rats of model group.This shows electro-ac upuncture can increase the expression level of Ang-lmRNA an d Tie-2 after cerebral ischemia-reperfusion in ipsilateral cerebral cortex.
Angiogenesis can arise after cerebral ischemia-reperfus ion.VEGF and Ang-1/Tie-2 participate in angiogenesis after cerebral ischemia-reperfusion injury.Electro-acupuncture adjust the process of angiogenesis in brain cortex after ce rebral ischemia-reperfusion injury,can effect urge angioge nesis in ischemia brain tissue and reduce the degree of ner ve function deficit.This could be carried by activating th e expression of VEGFmRNA and Ang-1mRNA/Tie-2.
引文
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