雌激素通过上调VEGF表达降低大鼠脑慢性低灌注诱导的微血管损伤  

Estrogen decreases vascular damage induced by chronic hypoperfusion through upregulating VEGF expression

作　　者：唐慧 张文丽 朱莹 张茜 王瑞敏 

机构地区：[1]华北理工大学医学研究中心神经生物学研究所,河北唐山063000 [2]华北理工大学附属医院病理科,河北唐山063000 [3]唐山市老年医学重点实验室,河北唐山063000

出　　处：《南方医科大学学报》2015年第11期1552-1556,共5页Journal of Southern Medical University

基　　金：国家自然科学基金(31171354);唐山市科技局项目(13130293z)~~

摘　　要：目的通过检测大鼠永久性结扎双侧颈总动脉(BCCAO)后不同时期脑微血管的病理变化以及生理剂量17-β-雌二醇(E2)替代治疗的影响,探讨E2替代治疗在慢性低灌注诱导的血管性痴呆发生发展中的作用及可能机制。方法实验动物随机分为BCCAO早期:sham(3 d),BCCAO 3 d组,BCCAO 3 d+E2组;BCCAO后晚期:sham(3月),BCCAO 3月和BCCAO 3月并持续给予E2组。采用免疫组织化学法检测各组Ig G的渗漏,电镜技术观察各组血管的超微结构;Western blot技术检测血管内皮生长因子(VEGF)的表达。结果免疫组化结果显示,与相应sham(3 d或3 m)组相比,BCCAO后3 d、3 m组皮层和海马CA1区可见大量损伤的血管被Ig G免疫染色包围;与BCCAO 3 d组相比,海马CA1区BCCAO 3 m组Ig G在血管周围的染色较弱;连续给予E2可显著降低血管Ig G的渗漏。电镜结果显示BCCAO 3 d和3月组海马CA1区血管周围严重水肿,血管轻度扩张及内皮细胞超微结构的损伤;给予E2可显著改善血管的超微结构。Western blot结果显示海马CA1区VEGF的表达于BCCAO后6 h,1 d显著增高,此后显著降低,于3 d达最低;BCCAO 3月时VEGF水平较sham(3月)组显著降低;E2可显著升高BCCAO后3 d或3月海马CA1区VEGF的表达。结论 BCCAO早期即可导致血管结构损伤,这种损伤可持续到BCCAO后3月;生理剂量E2替代治疗可能通过上调VEGF的蛋白表达降低BCCAO诱导的血管性痴呆。Objective To evaluate the effect of physiological dose 17-β-estrodiol（E2） replacement therapy on vascular dementia caused by cerebral chronic hypoperfusion. Methods The rats with bilateral common carotid artery occlusion（BCCAO）received E2 treatment starting from 3 days or 3 months after the operation. Ig G leakage into the brain parenchyma and the changes of microvascular ultrastructure following BCCAO were examined using immunohistochemistry and electron microscopy, respectively; Western blotting was used to detect the expression of vascular endothelial growth factor（VEGF）protein. Results Compared with the sham-operated groups, the rats at 3 days and 3 months after BCCAO showed extensive vascular damages surrounded by Ig G immunoreactivity in both the cortical and hippocampal CA1 regions. Stronger Ig G immunoreactivity in the hippocampal CA1 region was observed at 3 days after BCCAO than at 3 months, but no significant Ig G leakage was found in rats with continuous E2 treatment. Electron microscopy revealed severe edema around the blood vessels, mild vascular dilation, and endothelial cell damages at both 3 days and 3 months after BCCAO. E2 treatment markedly reduced the microvascular ultrastructural damages. Western blot analysis showed a significant increase in VEGF expression in the CA1 region at 6 h and 1 day after BCCAO followed by an obvious reduction till reaching the lowest level at 3days; VEGF expression remained low even at 3 months after BCCAO and was significantly increased by E2 treatment.Conclusions Vascular structural damage occurs early after BCCAO and can last for 3 months. E2 replacement therapy at physiological doses can reduce the incidence of BCCAO-induced vascular dementia by up-regulating VEGF expression.

关 键 词：双侧颈总动脉永久结扎 微血管 IgG VEGF 17-Β-雌二醇 

分 类 号：R749.13[医药卫生—神经病学与精神病学]