补肾活血法对血管性认知障碍大鼠血管新生的实验研究
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摘要
目的：血管新生是决定脑缺血病理损伤后缺血性神经元存活的关键因素,与认知障碍的程度密切相关。本课题从分子和细胞两个水平探讨补肾活血方——首乌益智胶囊通过调节VEGF-Notch/Delta级联信号通路,从而对血管性认知障碍大鼠血管新生产生的影响,为补肾活血法治疗血管性认知障碍提供初步的实验数据和理论依据。
方法：以SD大鼠为实验对象,采用大脑中动脉缺血再灌注法建立血管性认知障碍动物模型。将120只大鼠经Morris水迷宫实验筛选出100只,随机分为假手术组、模型组、脑复康组、首乌益智组。造模后药物干预4周,Morris水迷宫试验检测各组大鼠行为学改变,HE染色及透射电镜观察脑组织形态学变化,免疫组化法检测第Ⅷ因子表达以观察缺血脑组织微血管密度的改变,实时荧光定量PCR检测VEGF-Notch/Delta级联信号通路上Notch4、D114、VEGF、VEGFR-2等基因表达。
结果：形态学观察,造模后海马锥体细胞缺失、线粒体肿胀、血管管壁变薄,治疗后锥体细胞缺失减少,细胞器基本正常、血管周围水肿减轻。Morris水迷宫实验逃避潜伏期时间,模型组大鼠明显延长,与假手术组相比有极显著差异(P<0.01)。脑复康组、首乌益智组逃避潜伏期时间依次缩短,与假手术组比较,首乌益智组差异无显著性(P>0.05),脑复康组差异有极显著性(P<0.01)；与脑复康组比较,首乌益智组差异有极显著性(P<0.01)。缺血灶周围微血管密度方面,模型组、脑复康组、首乌益智组较假手术组依次升高；各组与假手术组相比,差异均有极显著性(P<0.01)；与模型组比较,脑复康组、首乌益智组差异均有极显著性(P<0.01)；与脑复康组比较,首乌益智组差异无显著性(P>0.05)。血管性认知障碍模型大鼠脑组织VEGF、VEGFR-2、Notch4、D114水平较假手术组大鼠升高,差异有显著性(P<0.01,P<0.05)。药物干预后,脑复康组和首乌益智组脑组织VEGF、VEGFR-2、Notch4、D114水平进一步升高；除VEGFR-2外,首乌益智组大鼠脑组织VEGF、Notch4、D114表达升高,与脑复康组相比存在显著差异(P<0.01,P<0.05)。在首乌益智胶囊干预的VCI模型大鼠的VEGF和D114之间存在着显著正相关性。
结论：补肾活血法通过对VCI大鼠VEGF-Notch/Delta级联信号通路的调节,精确调节脑组织缺血灶及其周围组织的血管新生,对受损神经元产生营养和修复作用,从而有效纠正脑缺血导致的认知障碍。并且,对缺血脑组织血管新生的调节作用,首乌益智胶囊明显优于脑复康。
Objective:Angiogenesis is the key factor for the ischemic neuron survival after cerebral ischemic injury and is closely correlated with the level of cognitive impairment. This study explored the effect of Shouwuyizhi Capsule on angiogenesis in rats with vascular cognitive impairment through the regulation of the VEGF-Notch/Delta cascade signaling pathway from molecular and cellular level, and therefore provides the preliminary experimental data and theoretical base for the treatment of tonifying the kidney and activating the blood for vascular cognitive impairment.
Method:SD rats were used and the VCI model was established with MCAO.100 rats were chosen from 120 rats by Morris water maze and randomly divided into sham operation group, model group, Naofukang group and Shouwuyizhi group. After 4 weeks'medication, the rats'behavioral change was detected by Morris water maze and the cerebral histomorphological change was observed by HE stain and transmission light microscope.Ⅷfactor expression was measured by immunohistochemistry method and the expression of the genes of Notch4, Delta4, VEGF, VEGFR-2 was measured using real time PCR.
Results:The escape escape latency of rats of model group was significantly longer than that of rats of shan group (P<0.01); The escape escape latency of rats of Naofukang group and Shouwuyizhi group were shortened successively.Compared with sham group,Shouwuyizhi group had no significant difference (P>0.05), while Naofukang group had the significant difference (P<0.01); Compared with Naofukang group, Shouwuyizhi group had the significant difference (P<0.01)。About the microvessel dencity of ischemia cerebral tissue,all of the other three groups were higher than sham group with the significant difference(P<0.01); Compared with model group,Naofukang group and Shouwuyizhi group had the significant difference (P<0.01); Shouwuyizhi group had no difference with Naofukang group (P>0.05)。The content of cerebral tissue of angiogenesis factors (VEGF,VEGFR-2, Notch4,D114) of rats model with vascular congnitive impairment were higher than the rats of sham group (P<0.01); After the treatment,the content of theses factors were further highter than model group.Except VEGFR-2,the content of VEGF、Notch4、D114 of Shouwuyizhi group were highter than Naofukang group (P<0.01, P<0.05).In Shouwuyizhi group,the contents of VEGF and that of D114 had significantly correlation (P<0.01).The content of serum anti-inflammatory cytokines ((IL-4, IL-10) of rats model with chronic inflammatory disease were lower than these of normal rats; the differences were very significant (P<0.01). After treatment, pro-inflammatory cytokine levels of the treatment group had decreased anti-inflammatory cytokine levels were elevated. At the regulation of IL-4, IL-8, IL-10, IL-1(3 the therapeutic effects of Jingangteng capsule group were better than GuizhiFuling capsule group and Shaofuzhuyu group, At the regulation of TNF-a, therapeutic effects of Guizhi Fuling Capsule medium dose group and Shaofuzhuyu group were better than Jingangteng capsule group.The expression of adhesions related immune molecules(TNF-α, TGF-β1, VEGF, ICAM-1, MMP-2) in model rats uterine tissue elevated above normal group, the differences were very significant (P<0.01) After treatment, expression of TNF-αTGF-β1 ICAM-1 in the treatment group had decreased, and MMP-2 had elevated. therapeutic effects of Guizhi Fuling Capsule medium dose group and Shaofuzhuyu group were better than Jingangteng capsule group (P<0.05). VEGF expression in each group reduced.
Conclusion:The treatment of tonifying the kidney and activating the blood could positively regulate the angiogenesis of the ischemic cerebral tissue and the surrounding tissue by regulating the VEGF-Notch/Delta cascade signaling pathway so as to nourish and repair the damaged neuron and effectively improve the cognitive impairment induced by the cerebral ischemia.
方法：以SD大鼠为实验对象,采用大脑中动脉缺血再灌注法建立血管性认知障碍动物模型。将120只大鼠经Morris水迷宫实验筛选出100只,随机分为假手术组、模型组、脑复康组、首乌益智组。造模后药物干预4周,Morris水迷宫试验检测各组大鼠行为学改变,HE染色及透射电镜观察脑组织形态学变化,免疫组化法检测第Ⅷ因子表达以观察缺血脑组织微血管密度的改变,实时荧光定量PCR检测VEGF-Notch/Delta级联信号通路上Notch4、D114、VEGF、VEGFR-2等基因表达。
结果：形态学观察,造模后海马锥体细胞缺失、线粒体肿胀、血管管壁变薄,治疗后锥体细胞缺失减少,细胞器基本正常、血管周围水肿减轻。Morris水迷宫实验逃避潜伏期时间,模型组大鼠明显延长,与假手术组相比有极显著差异(P<0.01)。脑复康组、首乌益智组逃避潜伏期时间依次缩短,与假手术组比较,首乌益智组差异无显著性(P>0.05),脑复康组差异有极显著性(P<0.01)；与脑复康组比较,首乌益智组差异有极显著性(P<0.01)。缺血灶周围微血管密度方面,模型组、脑复康组、首乌益智组较假手术组依次升高；各组与假手术组相比,差异均有极显著性(P<0.01)；与模型组比较,脑复康组、首乌益智组差异均有极显著性(P<0.01)；与脑复康组比较,首乌益智组差异无显著性(P>0.05)。血管性认知障碍模型大鼠脑组织VEGF、VEGFR-2、Notch4、D114水平较假手术组大鼠升高,差异有显著性(P<0.01,P<0.05)。药物干预后,脑复康组和首乌益智组脑组织VEGF、VEGFR-2、Notch4、D114水平进一步升高；除VEGFR-2外,首乌益智组大鼠脑组织VEGF、Notch4、D114表达升高,与脑复康组相比存在显著差异(P<0.01,P<0.05)。在首乌益智胶囊干预的VCI模型大鼠的VEGF和D114之间存在着显著正相关性。
结论：补肾活血法通过对VCI大鼠VEGF-Notch/Delta级联信号通路的调节,精确调节脑组织缺血灶及其周围组织的血管新生,对受损神经元产生营养和修复作用,从而有效纠正脑缺血导致的认知障碍。并且,对缺血脑组织血管新生的调节作用,首乌益智胶囊明显优于脑复康。
Objective:Angiogenesis is the key factor for the ischemic neuron survival after cerebral ischemic injury and is closely correlated with the level of cognitive impairment. This study explored the effect of Shouwuyizhi Capsule on angiogenesis in rats with vascular cognitive impairment through the regulation of the VEGF-Notch/Delta cascade signaling pathway from molecular and cellular level, and therefore provides the preliminary experimental data and theoretical base for the treatment of tonifying the kidney and activating the blood for vascular cognitive impairment.
Method:SD rats were used and the VCI model was established with MCAO.100 rats were chosen from 120 rats by Morris water maze and randomly divided into sham operation group, model group, Naofukang group and Shouwuyizhi group. After 4 weeks'medication, the rats'behavioral change was detected by Morris water maze and the cerebral histomorphological change was observed by HE stain and transmission light microscope.Ⅷfactor expression was measured by immunohistochemistry method and the expression of the genes of Notch4, Delta4, VEGF, VEGFR-2 was measured using real time PCR.
Results:The escape escape latency of rats of model group was significantly longer than that of rats of shan group (P<0.01); The escape escape latency of rats of Naofukang group and Shouwuyizhi group were shortened successively.Compared with sham group,Shouwuyizhi group had no significant difference (P>0.05), while Naofukang group had the significant difference (P<0.01); Compared with Naofukang group, Shouwuyizhi group had the significant difference (P<0.01)。About the microvessel dencity of ischemia cerebral tissue,all of the other three groups were higher than sham group with the significant difference(P<0.01); Compared with model group,Naofukang group and Shouwuyizhi group had the significant difference (P<0.01); Shouwuyizhi group had no difference with Naofukang group (P>0.05)。The content of cerebral tissue of angiogenesis factors (VEGF,VEGFR-2, Notch4,D114) of rats model with vascular congnitive impairment were higher than the rats of sham group (P<0.01); After the treatment,the content of theses factors were further highter than model group.Except VEGFR-2,the content of VEGF、Notch4、D114 of Shouwuyizhi group were highter than Naofukang group (P<0.01, P<0.05).In Shouwuyizhi group,the contents of VEGF and that of D114 had significantly correlation (P<0.01).The content of serum anti-inflammatory cytokines ((IL-4, IL-10) of rats model with chronic inflammatory disease were lower than these of normal rats; the differences were very significant (P<0.01). After treatment, pro-inflammatory cytokine levels of the treatment group had decreased anti-inflammatory cytokine levels were elevated. At the regulation of IL-4, IL-8, IL-10, IL-1(3 the therapeutic effects of Jingangteng capsule group were better than GuizhiFuling capsule group and Shaofuzhuyu group, At the regulation of TNF-a, therapeutic effects of Guizhi Fuling Capsule medium dose group and Shaofuzhuyu group were better than Jingangteng capsule group.The expression of adhesions related immune molecules(TNF-α, TGF-β1, VEGF, ICAM-1, MMP-2) in model rats uterine tissue elevated above normal group, the differences were very significant (P<0.01) After treatment, expression of TNF-αTGF-β1 ICAM-1 in the treatment group had decreased, and MMP-2 had elevated. therapeutic effects of Guizhi Fuling Capsule medium dose group and Shaofuzhuyu group were better than Jingangteng capsule group (P<0.05). VEGF expression in each group reduced.
Conclusion:The treatment of tonifying the kidney and activating the blood could positively regulate the angiogenesis of the ischemic cerebral tissue and the surrounding tissue by regulating the VEGF-Notch/Delta cascade signaling pathway so as to nourish and repair the damaged neuron and effectively improve the cognitive impairment induced by the cerebral ischemia.
引文
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