血脑屏障紧密连接损坏引起大鼠高血压性脑白质病变

The involvement of tight junction damage of the blood-brain barrier in hypertensive white matter lesions in rats

目的探讨易卒中型肾血管性高血压大鼠(stroke-prone renalvascular hypertensive rats,RHRSP)血脑屏障(blood-brain barrier,BBB)紧密连接(tight junction,TJ)变化引起脑白质病变(white matter lesions,WML)的机制。方法雄性SD大鼠90只,随机分为假手术组(n=15)和RHRSP组(n=75),定期监测血压,在4周、8周、12周、20周、30周分别进行WML分级,透射电镜观察白质区域血脑屏障超微结构,免疫荧光检测脑组织白蛋白漏出,Loyez染色观察神经纤维改变。结果模型组术后4周、8周血压明显升高(P<0.01),分别为(148.3±11.6)mm Hg、(169.9±10.7)mm Hg,12周为(188.9±13.6)mm Hg,此后血压趋于平稳;WML逐渐加重,胼胝体病变最明显,分级依次为(0.4±0.2)、(0.8±0.2)、(1.4±0.2)、(2.2±0.2)、(2.6±0.2);RHRSP 4周及8周TJ无明显变化,12周时27个中有8个、20周时24个中9个、30周时20个中有11个破坏;RHRSP 12周前脑实质及血管周围未见血浆白蛋白漏出,20周可见血管周围白蛋白漏出,30周可见颗粒状白蛋白漏出到脑实质内,白质区域以胼胝体及尾核漏出最明显;RHRSP 8周时出现神经纤维紊乱,12周可见空泡形成,20周可见明显的脑白质疏松,30周加重。结论RHRSP模型是合适的研究高血压性WML模型;长期高血压可以破坏BBB的TJ,从而引起血浆白蛋白的漏出,造成神经毒性,导致WML的发生。

Objective To explore the involvement of tight junctions （TJ） damage in hypertensive white matter lesions（WML） in Stroke-prone Renovascular Hypertensive Rats（RHRSP）. Methods Ninety male SD rats were randomly divided into RHRSP group （n=75） and sham operated control group（n=15）.The severity of WML was graded at 4, 8, 12 and 20 weeks after bilateral renal artery constriction, respectively. The ultrastructure of BBB was examined by using transmisson electron microscope. Immunofluorescence and Loyez staining were used to detect albumin exudation and nerve fibers, respectively. Results In the RHRSP group, blood pressure significantly increased at 4 （ 148.3 ± 11.6 mmHg） and 8 weeks（169.9 ± 10.7 mmHg） and then persisted at a high level after 12 weeks（188.9 ± 13.6 mm Hg） following bilateral renal artery constriction. WML increased gradually and was most prominent in the corpus callosum.In RHRSP, TJ remained intact between 4 and 8 weeks and was gradually damaged thereafter. The numbers of damaged TJ were 8 of 27, 9 of 24,11 of 20 at 12,20 and 30 weeks,respectively.In RHRSP, no plasma albumin leakage could be detected before 12 weeks. However, albumin extravasation was evident perivascularly at 20 weeks and diffused into brain parenchyma, especially, the corpus callosum and caudate nucleus at 30 weeks. In RHRSP, the nerve fiber was distorted at 8 weeks and then formed vacuoles at 12 weeks. Leukoaraiosis could be detected at 20 weeks and became more severe at 30 weeks. Conclusions RHRSP is an idea model for the study of hypertensive WML. Long-term hypertension may impair the TJ of BBB,cause leakage of ablubin and damage the brain tissue, thereby leading to WML.