亚低温后适应对树鼩局灶性脑缺血VEGF表达及神经元抗凋亡机制的研究
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摘要
[目的]观察树鼩血栓性脑缺血亚低温后适应对神经元、神经元微环境及其对皮层梗死面积的影响,研究缺血亚低温后适应对脑缺血保护效应,探讨血管内皮生长因子(endothelial vascular growth factor,VEGF)在基因水平、蛋白水平及受体在树鼩脑缺血以及低温后适应中的作用,揭示VEGF的表达调控在脑缺血亚低温后适应中的作用机制。
[方法]采用光化学反应诱导树鼩局灶性脑缺血,建立动物模型,在造模后6h采用局部降温的方法,使树鼩脑部温度降至31±0.5℃,并维持1h以建立树鼩局灶性脑缺血亚低温后适应组;使用外源性VEGF抗体分别在脑缺血造模结束后即刻、6h后注入树鼩小脑延髓池,以复制树鼩局灶性脑缺血VEGF抗体注射模型,如同时使用上述两种方法,则可建立脑缺血VEGF注射后亚低温后适应(Hypothermia Post Condition,HPC)模型,分别应用TUNEL(Terminal deoxynucleotidy transferase-mediated uridine5'-triphosphate-biotin nick end labeling,TUNEL)染色法、HE染色、TTC(2,3,5-triphenyltetrazolium chloride)染色、海马区微透析技术探讨缺血组、缺血后亚低温后适应组、缺血VEGF抗体注射组的缺血VEGF注射后亚低温后适应组各脑区神经细胞死亡改变、皮层梗死面积的变化及海马区神经元微环境的改变;应用RT-PCR(Reverse transcription-Polymerase Chain Reaction)技术、ELISA(Enzymelinked-immuno-sorbent assay)技术,研究VEGFmRNA、VEGF蛋白质及其受体在脑缺血后亚低温后适应中的变化。
[结果]脑缺血后,缺血组与VEGF抗体组、HPC组及联合使用VEGF抗体及HPC组的VEGFmRNA、VEGF蛋白、VEGF受体(VEGFR-1＼VEGFR-2)及海马CA1区、皮层神经细胞坏死与凋亡、海马局部神经元微环境及皮层梗死面积上均有显著性差异。在VEGFmRaNA检测中提示:海马VEGFmRNA含量较皮层高(P＜0.05),脑缺血后HPC使皮层VEGFmRNA于24h时含量明显增加(P＜0.05),72h时表达下降,而使用VEGF抗体组VEGFmRNA于72h时明显增加(P＜0.05);海马VEGFmRNA含量则表现为,HPC组缺血侧mRNA含量24h时低于缺血组(P＜0.05),并持续至72h;VEGF抗体组能明显减少对侧VEGFmRNA的含量;VEGF在海马及皮层中含量的检测提示:在脑缺血后皮层和海马中,VEGF的含量24h时均明显增加(P＜0.05),随时间延长有所下降(P＜0.05),HPC组在缺血后24h时显著增(P＜0.05),72h时下降与缺血组72h时无差异(P＞0.05),VEGF抗体组能明显抑制HPC及缺血所致的VEGF含量增加;TTC染色显示:VEGF抗体组皮层梗死面积显著增加(P＜0.05)达80%,HPC可显著降低皮层梗死面积(P＜0.05)达19.67%;海马局部微透析液离子分析提示:缺血后海马局部神经元细胞外液中Na~+浓度显著下降(P＜0.05),K~+浓度明显上升(P＜0.05),Ca~(2+)显著下降(P＜0.05);HPC在24h有助于抑制上述变化(P＜0.05),72h使上述变化加剧(P＜0.05)。HE染色提示:脑缺血后海马CA1区神经元坏死数明显增加(P＜0.05),HPC于24h时可使坏死细胞数显著下降(P＜0.05),但可增加72h的坏死细胞数,VEGF抗体组则在24h、72h均可增加缺血侧坏死细胞数;缺血同样可以使皮层缺血区神经细胞坏死数显著增加(P＜0.05),但对侧区除VEGF抗体组,神经细胞坏死仅出现于72h,其中24h时HPC可明显减少皮层神经细胞坏死,但72h可增加神经细胞坏死。TUNEL染色提示:脑缺血后缺血侧海马CA1区神经元凋亡24h时显著增加(P＜0.05),随时间延长凋亡细胞减少,但HPC组72h时神经元凋亡增加,72h HPC缺血+VEGF抗体组海马神经元凋亡显著低于HPC缺血组(P＜0.05);皮层神经细胞表现为:HPC可显著减少缺血后24h皮层神经细胞凋亡(P＜0.05),但随时间延长凋亡细胞数增加(P＜0.05),而缺血组,皮层神经细胞凋亡数随时间延长逐渐减少(P＜0.05)。ELISA检测VEGFR-1含量结果显示:缺血后VEGFR-1的含量显著升高(P＜0.05),且缺血侧低于对侧(P＜0.05);同时,VEGFR-1的含量于24h达高峰,HPC可增加缺血后VEGFR-1的含量。VEGFR-2含量检测结果示:缺血后VEGFR-2含量在脑和海马组织中显著增加(P＜0.05),并随时间延长持续增加(P＜0.05),HPC可显著增加VEGFR-2的含量(P＜0.05)。
[结论]①树鼩局灶性脑缺血HPC早期具有上调VEGF表达,抑制神经元凋亡和坏死以及减少梗死面积的作用。其机制可能与VEGF通过多条途径维持和改善神经元微环境的脑保护效应有关。②VEGF蛋白与VEGFmRNA的相互关系表明,HPC组缺血早期VEGF表达增强,而HPC后期VEGF表达下降可能是VEGF合成过程中的负反馈调节的结果,以致胞浆内mRaNA转录减少。③抑制VEGF作用可改变脑缺血后HPC的脑保护作用,证实HPC的脑保护作用与VEGF表达上调有关。
OBJECTIVE:To observe the changes of the neurons microenvironment,as weU as the effect of infarction area resulted fi'om hypothermia postcondition after thrombotic cerebral ischemia in Tree Shrews,to study effect on hypothermia postcondition cerebral ischemia.We explore the effect of VEGFmRNA,VEGF protein and its receptor on cerebral ischemia and hypothermic postcondition,and exposes the mechanism of VEGF expression and modulate on hypothermia postcondition.
METHODS:Cerebral ischemia was induced by photochemical reaction.The temperature of Tree Shrews' brain was lowered down to 31±0.5℃for 1 h by local temperature reduction method at 6h after ischemia,which was classified as the hypothermia postcondition group; the foreign VEGF antibody was instantly injected into cerebellomedullary cister at 6h after ischemia,which was classified as VEGF antibody injection group.When these two procedures were all executed,it would be classified as antibody injection+hypothermia postcondition group.The changes of neurons injury,infarction area and hippocampal microenvironment were studied in every group by TUNEL stain,HE stain,TTC and microdialysis in hippocampus;The changes of VEGFrnRNA,VEGF protein and receptor were investigated in hypothermic postcondition group through RT-PCK and ELISA technique.
RESULTS:The contents of VEGFmRNA,VEGF receptor(VEGFR-I\VEGFR-2),neurons necrosis and apoptosis in hippocampus CA1 and cortex,hippocampal microenvironment and cortical infarction area had markedly difference between every group.The result of VEGFmRNA indicated that the contents of VEGFmRNA in hippocampus was above cortex (P＜0.05).hypothermia postcondition increased significantly the contents of VEGFmRNA in cortex at 24h after ischemia(P＜0.05),whereas decreased at 72h.But the contents of VEGFmRNA obviously rose at 72h in VEGF antibody injection group(P＜0.05).The results of VEGFmRNA in ischemic hippocampus displayed that the contents of mRNA of hypothermia postcondition group were less than that ischemia control group(P＜0.05),and this change lasted at 72h,while VEGF antibody injection could markedly decrease the contents of VEGFmRNA in contra lateral to ischemia.The results of VEGFmRNA in hippocampus and cortex demonstrated that the contents of VEGFmRNA apparently increased in theses two regions(P＜0.05),while decreased with time(P＜0.05);It rascended markedly in HPhC group at 24h after ischemia(P＜0.05),but descended at 72h and had no difference with control group(P＞0.05).The VEGF antibody injection obviously inhibited increased VEGF resulted from HPC and ischemia.TTC stain showed that the infarction area enlarged to 80%in VEGF antibody group(P＜0.05),while in HPC group the infarction area markedly reduced to19.67%.The analysis of microdialysis in hippocampus suggested that in extracellular fluid the sodium concentration decreased markedly(P＜0.05),potassium concentration increased(P＜0.05) at 24h,calcium concentration decreased markedly (P＜0.05),while HPC helped to inhibit these changes(P＜0.05),intensified these at 72h (P＜0.05).HE stain showed that numbers of neuron necrosis in hippocampus CA1 region were increased(P＜0.05) after ischemia,.but it was decreased at 24h in HPC group(P＜0.05) while increased at 72h.The numbers of neuron necrosis rose at 24h,72h in VEGF antibody injection.Ischemia also made the numbers of cortical neuron necrosis to rise obviously (P＜0.05) as well as in contra lateral(P＜0.05).But in contra lateral,except VEGF antibody group,neuron necrosis only occurred at 72h.HPC could apparently alleviated neuron necrosis at 24h while deteriorated at 72h.TUNEL stain indicated that the neuron apoptosis in ischemic hippocampus CA1 region increased markedly at 24h after ischemia(P＜0.05) while decreased with time,but the neuron apoptosis increased at 72h in HPC group.The neuron apoptosis in HPC+VEGF antibody group were less than in HPC group(P＜0.05).Whereas in cortex,the neuron apoptosis decreased obviously in HPC group,but increased with time (P＜0.05).the neuron apoptosis in ischemia group gradually decreased(P＜0.05).ELISA investigation indicated that the contents of VEGFR-1 rose obviously(P＜0.05) after ischemia, and ischemic lateral was less than contra lateral(P＜0.05),at the same time,the contents of VEGFR-1 was at its peak at 24h after ischemia.The contents of VEGFR-2 were markedly increased in cortex and hippocampus(P＜0.05)and continuously increased with time(P＜0.05). HPC could obviously increase the contents of VEGFR-2(P＜0.05).
CONLUSION:①The instant protective effect of HPC can inhibit the neuronal apoptosis and necrosis by upregulating the expression of VEGF after thrombotic cerebral ischemia in Tree Shrews.Its mechanism maybe involved in that VEGF increase,improve the neuron microenvironment and inhibit neuronal apoptosis through multiple pathways,protect neurons from necrosis and apoptosis in hippocampus CA1 region and so on.②The relationship between VEGF protein and VEGFmRNA indicated that over expression of VEGF at ischemic early stage may stimulate mRNA transcription to decrease in cytoplasm through negative feedback,resulting in the reduction in VEGF contents at later stage.③Inhibition of VEGF function may reduce the neuroprotective effect in cerebral ischemia after HPC,HPC confirmed the neuroprotective effect throught VEGF upregulation.
[方法]采用光化学反应诱导树鼩局灶性脑缺血,建立动物模型,在造模后6h采用局部降温的方法,使树鼩脑部温度降至31±0.5℃,并维持1h以建立树鼩局灶性脑缺血亚低温后适应组;使用外源性VEGF抗体分别在脑缺血造模结束后即刻、6h后注入树鼩小脑延髓池,以复制树鼩局灶性脑缺血VEGF抗体注射模型,如同时使用上述两种方法,则可建立脑缺血VEGF注射后亚低温后适应(Hypothermia Post Condition,HPC)模型,分别应用TUNEL(Terminal deoxynucleotidy transferase-mediated uridine5'-triphosphate-biotin nick end labeling,TUNEL)染色法、HE染色、TTC(2,3,5-triphenyltetrazolium chloride)染色、海马区微透析技术探讨缺血组、缺血后亚低温后适应组、缺血VEGF抗体注射组的缺血VEGF注射后亚低温后适应组各脑区神经细胞死亡改变、皮层梗死面积的变化及海马区神经元微环境的改变;应用RT-PCR(Reverse transcription-Polymerase Chain Reaction)技术、ELISA(Enzymelinked-immuno-sorbent assay)技术,研究VEGFmRNA、VEGF蛋白质及其受体在脑缺血后亚低温后适应中的变化。
[结果]脑缺血后,缺血组与VEGF抗体组、HPC组及联合使用VEGF抗体及HPC组的VEGFmRNA、VEGF蛋白、VEGF受体(VEGFR-1＼VEGFR-2)及海马CA1区、皮层神经细胞坏死与凋亡、海马局部神经元微环境及皮层梗死面积上均有显著性差异。在VEGFmRaNA检测中提示:海马VEGFmRNA含量较皮层高(P＜0.05),脑缺血后HPC使皮层VEGFmRNA于24h时含量明显增加(P＜0.05),72h时表达下降,而使用VEGF抗体组VEGFmRNA于72h时明显增加(P＜0.05);海马VEGFmRNA含量则表现为,HPC组缺血侧mRNA含量24h时低于缺血组(P＜0.05),并持续至72h;VEGF抗体组能明显减少对侧VEGFmRNA的含量;VEGF在海马及皮层中含量的检测提示:在脑缺血后皮层和海马中,VEGF的含量24h时均明显增加(P＜0.05),随时间延长有所下降(P＜0.05),HPC组在缺血后24h时显著增(P＜0.05),72h时下降与缺血组72h时无差异(P＞0.05),VEGF抗体组能明显抑制HPC及缺血所致的VEGF含量增加;TTC染色显示:VEGF抗体组皮层梗死面积显著增加(P＜0.05)达80%,HPC可显著降低皮层梗死面积(P＜0.05)达19.67%;海马局部微透析液离子分析提示:缺血后海马局部神经元细胞外液中Na~+浓度显著下降(P＜0.05),K~+浓度明显上升(P＜0.05),Ca~(2+)显著下降(P＜0.05);HPC在24h有助于抑制上述变化(P＜0.05),72h使上述变化加剧(P＜0.05)。HE染色提示:脑缺血后海马CA1区神经元坏死数明显增加(P＜0.05),HPC于24h时可使坏死细胞数显著下降(P＜0.05),但可增加72h的坏死细胞数,VEGF抗体组则在24h、72h均可增加缺血侧坏死细胞数;缺血同样可以使皮层缺血区神经细胞坏死数显著增加(P＜0.05),但对侧区除VEGF抗体组,神经细胞坏死仅出现于72h,其中24h时HPC可明显减少皮层神经细胞坏死,但72h可增加神经细胞坏死。TUNEL染色提示:脑缺血后缺血侧海马CA1区神经元凋亡24h时显著增加(P＜0.05),随时间延长凋亡细胞减少,但HPC组72h时神经元凋亡增加,72h HPC缺血+VEGF抗体组海马神经元凋亡显著低于HPC缺血组(P＜0.05);皮层神经细胞表现为:HPC可显著减少缺血后24h皮层神经细胞凋亡(P＜0.05),但随时间延长凋亡细胞数增加(P＜0.05),而缺血组,皮层神经细胞凋亡数随时间延长逐渐减少(P＜0.05)。ELISA检测VEGFR-1含量结果显示:缺血后VEGFR-1的含量显著升高(P＜0.05),且缺血侧低于对侧(P＜0.05);同时,VEGFR-1的含量于24h达高峰,HPC可增加缺血后VEGFR-1的含量。VEGFR-2含量检测结果示:缺血后VEGFR-2含量在脑和海马组织中显著增加(P＜0.05),并随时间延长持续增加(P＜0.05),HPC可显著增加VEGFR-2的含量(P＜0.05)。
[结论]①树鼩局灶性脑缺血HPC早期具有上调VEGF表达,抑制神经元凋亡和坏死以及减少梗死面积的作用。其机制可能与VEGF通过多条途径维持和改善神经元微环境的脑保护效应有关。②VEGF蛋白与VEGFmRNA的相互关系表明,HPC组缺血早期VEGF表达增强,而HPC后期VEGF表达下降可能是VEGF合成过程中的负反馈调节的结果,以致胞浆内mRaNA转录减少。③抑制VEGF作用可改变脑缺血后HPC的脑保护作用,证实HPC的脑保护作用与VEGF表达上调有关。
OBJECTIVE:To observe the changes of the neurons microenvironment,as weU as the effect of infarction area resulted fi'om hypothermia postcondition after thrombotic cerebral ischemia in Tree Shrews,to study effect on hypothermia postcondition cerebral ischemia.We explore the effect of VEGFmRNA,VEGF protein and its receptor on cerebral ischemia and hypothermic postcondition,and exposes the mechanism of VEGF expression and modulate on hypothermia postcondition.
METHODS:Cerebral ischemia was induced by photochemical reaction.The temperature of Tree Shrews' brain was lowered down to 31±0.5℃for 1 h by local temperature reduction method at 6h after ischemia,which was classified as the hypothermia postcondition group; the foreign VEGF antibody was instantly injected into cerebellomedullary cister at 6h after ischemia,which was classified as VEGF antibody injection group.When these two procedures were all executed,it would be classified as antibody injection+hypothermia postcondition group.The changes of neurons injury,infarction area and hippocampal microenvironment were studied in every group by TUNEL stain,HE stain,TTC and microdialysis in hippocampus;The changes of VEGFrnRNA,VEGF protein and receptor were investigated in hypothermic postcondition group through RT-PCK and ELISA technique.
RESULTS:The contents of VEGFmRNA,VEGF receptor(VEGFR-I\VEGFR-2),neurons necrosis and apoptosis in hippocampus CA1 and cortex,hippocampal microenvironment and cortical infarction area had markedly difference between every group.The result of VEGFmRNA indicated that the contents of VEGFmRNA in hippocampus was above cortex (P＜0.05).hypothermia postcondition increased significantly the contents of VEGFmRNA in cortex at 24h after ischemia(P＜0.05),whereas decreased at 72h.But the contents of VEGFmRNA obviously rose at 72h in VEGF antibody injection group(P＜0.05).The results of VEGFmRNA in ischemic hippocampus displayed that the contents of mRNA of hypothermia postcondition group were less than that ischemia control group(P＜0.05),and this change lasted at 72h,while VEGF antibody injection could markedly decrease the contents of VEGFmRNA in contra lateral to ischemia.The results of VEGFmRNA in hippocampus and cortex demonstrated that the contents of VEGFmRNA apparently increased in theses two regions(P＜0.05),while decreased with time(P＜0.05);It rascended markedly in HPhC group at 24h after ischemia(P＜0.05),but descended at 72h and had no difference with control group(P＞0.05).The VEGF antibody injection obviously inhibited increased VEGF resulted from HPC and ischemia.TTC stain showed that the infarction area enlarged to 80%in VEGF antibody group(P＜0.05),while in HPC group the infarction area markedly reduced to19.67%.The analysis of microdialysis in hippocampus suggested that in extracellular fluid the sodium concentration decreased markedly(P＜0.05),potassium concentration increased(P＜0.05) at 24h,calcium concentration decreased markedly (P＜0.05),while HPC helped to inhibit these changes(P＜0.05),intensified these at 72h (P＜0.05).HE stain showed that numbers of neuron necrosis in hippocampus CA1 region were increased(P＜0.05) after ischemia,.but it was decreased at 24h in HPC group(P＜0.05) while increased at 72h.The numbers of neuron necrosis rose at 24h,72h in VEGF antibody injection.Ischemia also made the numbers of cortical neuron necrosis to rise obviously (P＜0.05) as well as in contra lateral(P＜0.05).But in contra lateral,except VEGF antibody group,neuron necrosis only occurred at 72h.HPC could apparently alleviated neuron necrosis at 24h while deteriorated at 72h.TUNEL stain indicated that the neuron apoptosis in ischemic hippocampus CA1 region increased markedly at 24h after ischemia(P＜0.05) while decreased with time,but the neuron apoptosis increased at 72h in HPC group.The neuron apoptosis in HPC+VEGF antibody group were less than in HPC group(P＜0.05).Whereas in cortex,the neuron apoptosis decreased obviously in HPC group,but increased with time (P＜0.05).the neuron apoptosis in ischemia group gradually decreased(P＜0.05).ELISA investigation indicated that the contents of VEGFR-1 rose obviously(P＜0.05) after ischemia, and ischemic lateral was less than contra lateral(P＜0.05),at the same time,the contents of VEGFR-1 was at its peak at 24h after ischemia.The contents of VEGFR-2 were markedly increased in cortex and hippocampus(P＜0.05)and continuously increased with time(P＜0.05). HPC could obviously increase the contents of VEGFR-2(P＜0.05).
CONLUSION:①The instant protective effect of HPC can inhibit the neuronal apoptosis and necrosis by upregulating the expression of VEGF after thrombotic cerebral ischemia in Tree Shrews.Its mechanism maybe involved in that VEGF increase,improve the neuron microenvironment and inhibit neuronal apoptosis through multiple pathways,protect neurons from necrosis and apoptosis in hippocampus CA1 region and so on.②The relationship between VEGF protein and VEGFmRNA indicated that over expression of VEGF at ischemic early stage may stimulate mRNA transcription to decrease in cytoplasm through negative feedback,resulting in the reduction in VEGF contents at later stage.③Inhibition of VEGF function may reduce the neuroprotective effect in cerebral ischemia after HPC,HPC confirmed the neuroprotective effect throught VEGF upregulation.
引文
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