Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

Miguel D'haeseleer, Roel Beelen, Yves Fierens, Melissa Cambron, Anne-Marie Vanbinst, Christian Verborgh, Johan Demey, Jacques De Keyser*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    64 Citations (Scopus)

    Abstract

    Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.

    Original languageEnglish
    Pages (from-to)5654-5658
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume110
    Issue number14
    DOIs
    Publication statusPublished - 2-Apr-2013

    Keywords

    • WHITE-MATTER DAMAGE
    • COGNITIVE IMPAIRMENT
    • DANISH PATIENTS
    • PLASMA-LEVELS
    • DISEASE
    • BRAIN
    • HYPOXIA
    • AXONS
    • PATHOGENESIS
    • PATHOLOGY

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