脑缺血后N-myc下游调控基因2保护血脑屏障完整性

N-myc downstream-regulated gene 2 protects blood-brain barrier integrity following cerebral ischemia

脑缺血后血脑屏障(BBB)的破坏与外周细胞向脑内浸润、病孔损形成与进展、以及临床病程恶化密切相关。目前BBB完整性的调控机制,尤其是在永久性缺血后的调控机制尚未明确。本研究使用小鼠永久性脑缺血模型进行相关研究,结果显示,星形胶质细胞N-myc下游调控基因2(NDRG2)可能是缺血性脑卒中后BBB通透性的调控分子,该分子与分化和应激相关。免疫组化显示,在永久性大脑中动脉闭塞(MCAO)后,NDRG2在星形胶质细胞中的表达显著增加。敲除NDRG2基因,脑梗死体积增加,免疫细胞在缺血同侧大脑半球积聚增加。MCAO后,NDRG2基因敲除小鼠缺血侧皮质的缺血灶内及灶周血管周围区域内的血清蛋白(包括纤维蛋白原和免疫球蛋白)的外渗增强此之,MCAO后NDRG2基因敲除小鼠体内基质金属蛋白酶(MMPs)的表达也显著增加。在细胞培养中,NDRG2-/-星形胶质细胞中MMP-3的表达和分泌增加,这种增加可被腺病毒介导的NDRG2再表达所逆转。综上所述,脑缺血后,星形胶质细胞内的NDRG2可能通过调节MMP的表达,而在BBB通透性的调节和免疫细胞浸润中起到重要作用。

Disruption of the blood-brain barrier(BBB)following cerebral ischemia is closely related to the infiltration of peripheral cells into the brain,progression of lesion formation,and clinical exacerbation.However,the mechanism that regulates BBB integrity,especially after permanent ischemia,remains unclear.Here,we present evidence that astrocytic N-myc downstream-regulated gene 2(NDRG2),a differentiation-and stress-associated molecule,may function as a modulator of BBB permeability following ischemic stroke,using a mouse model of permanent cerebral ischemia.Immunohistological analysis showed that the expression of NDRG2 increases dominantly in astrocytes following permanent middle cerebral artery occlusion(MCAO).Genetic deletion of Ndrg2 exhibited enhanced levels of infarct volume and accumulation of immune cells into the ipsilateral brain hemisphere following ischemia.Extravasation of serum proteins including fibrinogen and immunoglobulin,after MCAO,was enhanced at the ischemic core and perivascular region of the peri-infarct area in the ipsilateral cortex of Ndrg2-deficient mice.Furthermore,the expression of matrix metalloproteinases(MMPs)after MCAO markedly increased in Ndrg2-/-mice.In culture,expression and secretion of MMP-3 was increased in Ndrg2-/-astrocytes,and this increase was reversed by adenovirus-mediated re-expression of NDRG2.These findings suggest that NDRG2,expressed in astrocytes,may play a critical role in the regulation of BBB permeability and immune cell infiltration through the modulation of MMP expression following cerebral ischemia.