Abstract：
Hypertension is a leading cause of cerebral small vessel disease (CSVD) and vascular dementia in elderly individuals. We aimed to assess cerebral perfusion and dynamic changes in brain structure in stroke-prone renovascular hypertensive rats (RHRSPs) with different durations of hypertension and to investigate whether they have pathophysiological features similar to those of humans with CSVD. The RHRSP model was established using the two-kidney, two-clip (2k2c) method, and the Morris water maze (MWM) test, MRI, immunohistochemistry, and biochemical analysis were performed at multiple time points for up to six months following the 2k2c operation. Systolic blood pressure was significantly greater in the RHRSP group than in the sham-operated group at week 4 post-surgery and continued to increase over time, leading to cognitive decline by week 20. Arterial spin labeling revealed cerebral hypoperfusion in the RHRSP group at 8 weeks, accompanied by vascular remodeling and decreased vessel density. Diffusion tensor imaging and Luxol fast blue staining indicated that white matter disintegration and demyelination gradually progressed in the corpus callosum and that myelin basic protein levels decreased. Eight weeks after surgery, blood-brain barrier (BBB) leakage into the corpus callosum was observed. The albumin leakage area was negatively correlated with the myelin sheath area (r=-0.88, p<0.001). RNA-seq analysis revealed downregulation of most angiogenic genes and upregulation of antiangiogenic genes in the corpus callosum of RHRSPs 24 weeks after surgery. RHRSPs developed cerebral hypoperfusion, BBB disruption, spontaneous white matter damage, and cognitive impairment as the duration of hypertension increased. RHRSPs share behavioral and neuropathological characteristics with CSVD patients, making them suitable animal models for preclinical trials related to CSVD.
摘要：
高血压是老年人脑小血管病（CSVD）和血管性痴呆的主要原因。我们旨在评估高血压持续时间不同的易发性肾血管性高血压大鼠（RHRSP）的脑灌注和脑结构的动态变化，并研究它们是否具有与CSVD患者相似的病理生理特征。使用双肾建立RHRSP模型，双夹子(2k2c)方法，和莫里斯水迷宫（MWM）测试，MRI,免疫组织化学，和生化分析在2k2c手术后的多个时间点进行长达6个月。术后第4周，RHRSP组收缩压明显高于假手术组，并随时间持续升高，导致认知能力下降到第20周。动脉自旋标记显示RHRSP组在8周时脑灌注不足，伴有血管重塑和血管密度降低。扩散张量成像和Luxol快速蓝染色表明call体白质崩解和脱髓鞘逐渐发展，髓鞘碱性蛋白水平降低。手术后八周,观察到血脑屏障（BBB）渗入call体。白蛋白渗漏面积与髓鞘面积呈负相关(r=-0.88,p<0.001)。RNA-seq分析显示，手术后24周，RHRSP的call体大多数血管生成基因下调，抗血管生成基因上调。RHRSP出现脑灌注不足,BBB中断,自发性白质损伤，随着高血压持续时间的增加，认知障碍。RHRSP与CSVD患者具有共同的行为和神经病理学特征，使它们成为与CSVD相关的临床前试验的合适动物模型。
