Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, via Fossato di Mortara n 74, 44121, Ferrara, Italy.
Department of Life Science and Biotechnology, University of Ferrara, Ferrara, Italy.
Mol Med. 2018 Aug 9;24(1):42. doi: 10.1186/s10020-018-0043-4.
Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Several observations support interactions between vascular and neurodegenerative mechanisms in multiple sclerosis (MS). To investigate the contribution of the extracranial venous compartment, we analysed expression profiles of internal jugular vein (IJV), which drains blood from CNS, and related plasma protein levels.
We studied a group of MS patients (n = 19), screened by echo-color Doppler and magnetic resonance venography, who underwent surgical reconstruction of IJV for chronic cerebrospinal venous insufficiency (CCSVI). Microarray-based transcriptome analysis was conducted on specimens of IJV wall from MS patients and from subjects undergoing carotid endarterectomy, as controls. Protein levels were determined by multiplex assay in: i) jugular and peripheral plasma from 17 MS/CCSVI patients; ii) peripheral plasma from 60 progressive MS patients, after repeated sampling and iii) healthy individuals.
Of the differentially expressed genes (≥ 2 fold-change, multiple testing correction, P < 0.05), the immune-related CD86 (8.5 fold-change, P = 0.002) emerged among the up regulated genes (N = 409). Several genes encoding HOX transcription factors and histones potentially regulated by blood flow, were overexpressed. Smooth muscle contraction and cell adhesion processes emerged among down regulated genes (N = 515), including the neuronal cell adhesion L1CAM as top scorer (5 fold-change, P = 5 × 10). Repeated measurements in jugular/peripheral plasma and overtime in peripheral plasma showed conserved individual plasma patterns for immune-inflammatory (CCL13, CCL18) and adhesion (NCAM1, VAP1, SELL) proteins, despite significant variations overtime (SELL P < 0.0001). Both age and MS disease phenotypes were determinants of VAP1 plasma levels. Data supported cerebral related-mechanisms regulating ANGPT1 levels, which were remarkably lower in jugular plasma and correlated in repeated assays but not between jugular/peripheral compartments.
This study provides for the first time expression patterns of the IJV wall, suggesting signatures of altered vascular mRNA profiles in MS disease also independently from CCSVI. The combined transcriptome-protein analysis provides intriguing links between IJV wall transcript alteration and plasma protein expression, thus highlighting proteins of interest for MS pathophysiology.
多发性硬化症（MS）是一种中枢神经系统（CNS）的炎症性、脱髓鞘和退行性疾病。有几项观察结果支持血管和神经退行性机制在多发性硬化症（MS）中的相互作用。为了研究颅外静脉腔隙的贡献，我们分析了引流 CNS 血液的颈内静脉（IJV）的表达谱，并检测了相关血浆蛋白水平。
我们研究了一组 MS 患者（n=19），他们通过回声彩色多普勒和磁共振静脉造影筛查，因慢性脑脊髓静脉功能不全（CCSVI）而行 IJV 手术重建。对 MS 患者和颈动脉内膜切除术患者的 IJV 壁标本进行基于微阵列的转录组分析。通过对 17 名 MS/CCSVI 患者的颈内和外周血浆、60 名进展性 MS 患者的外周血浆（重复取样后）和健康个体的外周血浆进行多重检测，确定蛋白质水平。
差异表达基因（≥2 倍变化，多重检测校正，P<0.05）中，免疫相关的 CD86（8.5 倍变化，P=0.002）在上调基因（N=409）中脱颖而出。几个编码 HOX 转录因子和潜在受血流调节的组蛋白的基因表达上调。下调基因（N=515）中出现平滑肌收缩和细胞黏附过程，包括神经元细胞黏附 L1CAM，得分最高（5 倍变化，P=5×10）。尽管随时间有显著变化，但颈内/外周血浆的重复测量和外周血浆的随时间变化均显示出免疫炎症（CCL13、CCL18）和黏附（NCAM1、VAP1、SELL）蛋白的个体血浆模式保持一致。SELL P<0.0001）。年龄和 MS 疾病表型都是 VAP1 血浆水平的决定因素。数据支持调节血管生成素 1（ANGPT1）水平的脑相关机制，该蛋白在颈内静脉血浆中显著降低，且在重复检测中相关，但不在颈内/外周间隙之间相关。
这项研究首次提供了 IJV 壁的表达模式，表明 MS 疾病中存在血管 mRNA 谱改变的特征，也与 CCSVI 无关。综合转录组-蛋白质分析为 IJV 壁转录改变与血浆蛋白表达之间提供了有趣的联系，从而突出了对 MS 病理生理学有意义的蛋白质。
