Objective: To explore the histopathology, monocytes phenotypes and brain mRNA transcription of angiogenic and atherogenic factors preliminarily in spontaneous hypertensive rats (SHRs) fed with high salt diet and subjected to chronic focal hypoperfusion. Methods: A total of 21 SHRs were randomly assigned into SHR with normal diet (SHR-ND group, n=7), SHR fed with high salt (8%) chows (SHR-HSD group, n=14) groups. After induction of high salt diet for 20 weeks, unilateral carotid artery occlusion was applied to one half of SHR-HSD (SHR-HSD-UCAO, n=7) group for 10 weeks to mimic chronic focal cerebral hypoperfusion. The neuropathology, monocytes phenotypes and brain transcription of fibroblast growth factor (FGF-b), platelet-derived endothelial cell growth factor (PD-ECGF), angiogenin (ANG), transforming growth factor-β (TGF-β) and vascular endothelial growth factor A (VEGF-A) among three groups were compared. Results: The systolic blood pressure ((246±12) mmHg vs (220±16) mmHg, P=0.0291, 1 mmHg=0.133 kPa) and diastolic blood pressure ((189±15) mmHg vs (164±12) mmHg, P=0.0143) of SHR-HSD group were elevated significantly compared with those of SHR-ND group. Compared with normotensive Wistar-Kyoto (WKY), SHR-ND, SHR-HSD and SHR-HSD-UCAO groups demonstrated lipohyalinosis, vessel wall thickening, lumen narrowing and multiple enlarged perivascular space and diffuse disarrangement of nerve fiber and myelin vacuolation in corpus callosum pathologically. The ratio of CD11b(+) CD68(+) monocytes in peripheral blood of SHR-HSD group was higher compared with both SHR-ND and SHR-HSD-UCAO groups (P=0.000 8). The mean inflorescence index (MFI) of CD86 and CD206 showd considerable decline in SHR-HSD-UCAO group compared with those of SHR-HSD group (P=0.018 7 and 0.016 8, respectively). The CD86 MFI of CD11b+CD68+ monocytes in SHR-HSD-UCAO group was remarkably higher than that of SHR-ND and SHR-HSD groups (P=0.000 5). Compared with SHR-ND and SHR-HSD groups, the brain mRNA transcription of angiogenic factors including PD-ECGF and ANG were down-regulated (P=0.004 6 and 0.000 2, respectively), while the atherogenic factors including TGF-β and VEGF-A were up-regulated in SHR-HSD-UCAO group (P<0.000 1 and P=0.045, respectively). Conclusion: SHR-HSD-UCAO group shares the pathophysiological characteristics with advanced stage arteriosclerotic cerebral small vessel disease (aCSVD), including neuropathology, imbalanced circulating monocytes phenotypes and down-regulated angiogenic factors.
目的： 探究自发性高血压大鼠（SHR）高盐饮食合并慢性单侧颈内动脉闭塞模型的组织病理、单核细胞功能表型、脑组织动脉硬化相关血管因子转录改变。 方法： 21只6周龄SHR按照简单随机法直接抽样分成正常饮食组（SHR-ND，n=7）、高盐饮食组（SHR-HSD，n=14，予以8%高盐饲料喂养），在高盐饮食诱导20周后按照简单随机法直接抽样分配一半SHR-HSD予以施行单侧颈内动脉闭塞术（SHR-HSD-UCAO，n=7）并维持10周以模拟慢性局灶性低灌注，比较三组间脑组织病理学、外周血单核细胞亚型、脑组织中动脉硬化相关血管因子mRNA转录水平改变。 结果： SHR-HSD收缩压[（246±12）mmHg比（220±16）mmHg，P=0.029 1，1 mmHg=0.133 kPa]和舒张压[（189±15）mmHg比（164±12）mmHg，P=0.014 3]均明显高于SHR-ND。在组织病理学上，SHR-ND、SHR-HSD和SHR-HSD-UCAO三组均可见小动脉脂质玻璃样变性、管壁增厚、管腔缩窄、多发扩大的血管周围间隙、胼胝体神经纤维结构疏松和髓鞘空泡化改变。SHR-HSD外周血中CD11b(+)CD68(+)单核细胞比例明显高于SHR-ND和SHR-HSD-UCAO（P=0.000 8），而SHR-HSD-UCAO中促炎亚型标志物CD86（P=0.018 7）和抗炎亚型标志物CD206（P=0.016 8）的平均荧光强度（MFI）均低于SHR-HSD；在脾脏中，SHR-HSD-UCAO的CD11b(+)CD68(+)单核细胞CD86的MFI明显高于SHR-ND和SHR-HSD（P=0.000 5）。SHR-HSD-UCAO脑组织中促血管新生因子血小板衍生的内皮细胞生长因子（PD-ECGF）（P=0.004 6）和血管生成素（ANG）（P=0.000 2）的mRNA转录水平较SHR-ND和SHR-HSD下调，而转化生长因子（TGF-β）（P<0.000 1）和血管内皮生长因子（VEGF-A）（P=0.045）的mRNA转录水平均较SHR-ND和SHR-HSD显著上调。 结论： 高盐合并局灶性低灌注的SHR可诱导大鼠小动脉硬化、血管周围间隙扩大、脑白质疏松等病理改变，并伴随循环单核细胞免疫表型失衡、促血管新生因子转录下调，SHR-HSD-UCAO值得作为中晚期小动脉硬化型脑小血管病（aCSVD）疾病动物模型进一步探索。.
Keywords: Angiogenesis; Arteriolosclerosis; Cerebral small vessel disease; Disease animal model; High salt.