Distinct Brain Proteomic Signatures in Cerebral Small Vessel Disease Rat Models of Hypertension and Cerebral Amyloid Angiopathy.
Distinct Brain Proteomic Signatures in Cerebral Small Vessel Disease Rat Models of Hypertension and Cerebral Amyloid Angiopathy.
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DOI：
10.1093/jnen/nlac057
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发表时间：
2022-07
影响因子：
3.2
通讯作者：
Joseph M Schrader;Aleksandra Stanisavljevic;Feng Xu;W. V. Van Nostrand
中科院分区：
文献类型：
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作者：
Joseph M Schrader;Aleksandra Stanisavljevic;Feng Xu;W. V. Van Nostrand
脑小血管疾病 (CSVD) 是血管性认知障碍和痴呆的主要原因，可由多种病因引起。脑淀粉样血管病（CAA）和高血压（HTN）在老年人群中普遍存在，可导致脑微出血、大出血和白质损伤。然而，人们对它们各自的潜在机制和分子事件知之甚少。在这里，我们发现 CAA 1 型转基因大鼠模型 (rTg-DI) 表现出血管周围炎症，这是自发性高血压脑卒中倾向 (SHR-SP) 高血压大鼠模型所缺乏的。另外，SHR-SP 大鼠显示小动脉血管周围空间显着扩张。比较蛋白质组学分析显示，共享的改变蛋白很少，其中关键蛋白如 rTg-DI 大鼠特有的 ANXA3、H2A 和 HTRA1，以及 SHR-SP 大鼠特有的 Nt5e、Flot-1 和 Flot-2。免疫标记证实 ANXA3、HTRA1 和中性粒细胞胞外捕获蛋白的上调与 rTg-DI 大鼠明显相关。通路分析预测 rTg-DI 大鼠脑中 TGF-β1 和 TNFα 激活，而 SHR-SP 大鼠脑中胰岛素信号传导减弱。因此，我们报告了 SHR-SP 和 rTg-DI 大鼠模型中与不同脑血管病理相关的不同蛋白质特征，并为这些不同形式的 CSVD 提供了新的机制见解。
Cerebral small vessel diseases (CSVDs) are prominent contributors to vascular cognitive impairment and dementia and can arise from a range of etiologies. Cerebral amyloid angiopathy (CAA) and hypertension (HTN), both prevalent in the elderly population, lead to cerebral microhemorrhages, macrohemorrhages, and white matter damage. However, their respective underlying mechanisms and molecular events are poorly understood. Here, we show that the transgenic rat model of CAA type 1 (rTg-DI) exhibits perivascular inflammation that is lacking in the spontaneously hypertensive stroke-prone (SHR-SP) rat model of HTN. Alternatively, SHR-SP rats display notable dilation of arteriolar perivascular spaces. Comparative proteomics analysis revealed few shared altered proteins, with key proteins such as ANXA3, H2A, and HTRA1 unique to rTg-DI rats, and Nt5e, Flot-1 and Flot-2 unique to SHR-SP rats. Immunolabeling confirmed that upregulation of ANXA3, HTRA1, and neutrophil extracellular trap proteins were distinctly associated with rTg-DI rats. Pathway analysis predicted activation of TGF-β1 and TNFα in rTg-DI rat brain, while insulin signaling was reduced in the SHR-SP rat brain. Thus, we report divergent protein signatures associated with distinct cerebral vessel pathologies in the SHR-SP and rTg-DI rat models and provide new mechanistic insight into these different forms of CSVD.