Changes in expression profiles of internal jugular vein wall and plasma protein levels in multiple sclerosis

Giovanna Marchetti,Nicole Ziliotto,Erica Menegatti,Fabio Manfredini,Barbara Lunghi,Silvia Meneghetti,Francesco Mascoli,Nino Basaglia,Paolo Zamboni,Francesco Bernardi,Ilaria Bartolomei,Sofia Straudi,Fabrizio Salvi,Massimo Pedriali,Rebecca Voltan,Marcello Baroni

doi:10.1186/s10020-018-0043-4

Giovanna Marchetti, Nicole Ziliotto + Show 14 more

Open Access

https://doi.org/10.1186/s10020-018-0043-4

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Abstract

BackgroundMultiple 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.MethodsWe 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.ResultsOf 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− 4).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.ConclusionsThis 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.

Highlights

Multiple sclerosis (MS) is an inflammatory demyelinating and degenerative disorder of the central nervous system (CNS) (Noseworthy et al 2000) for which several genetic, epigenetic and environmental components have been proposed to participate through complex interactions (Amato et al 2018; Olsson et al 2017)
To shed light on vascular gene expression changes in MS with associated chronic cerebrospinal venous insufficiency (CCSVI), we focused on internal jugular vein (IJV), which drains blood from the brain
The 19 patients belonged to a cohort of patients who were eligible for surgical reconstruction of internal jugular vein by angioplasty and entered the study approved by the Ethical Committee of the S

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Multiple sclerosis (MS) is an inflammatory demyelinating and degenerative disorder of the central nervous system (CNS) (Noseworthy et al 2000) for which several genetic, epigenetic and environmental components have been proposed to participate through complex interactions (Amato et al 2018; Olsson et al 2017). The vascular cerebral system, and the venous compartment, early received attention because of venous thrombosis in the brain of MS patients, and plaques of demyelination development around venules and perivascular infiltrations of inflammatory cells just small and medium size venous of CNS (Adams 1988). A perspective of reduced blood supply to the brain (D'haeseleer et al 2015), further argue for the relevance of the vascular component in the disease

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