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

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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

ET-1 plasma levels from the internal jugular vein and a peripheral vein in subjects with MS and control subjects (bar indicates the mean). (§In the control group, there was an outlier with high ET-1 levels, but his internal jugular vein/peripheral vein ET-1 ratio was 0.98, indicating that this was not caused by ET-1 coming from the brain.)

Fig. 2.

Immunostaining for ET-1. Representative photograph a chronic active MS plaque (darker area) and surrounding NAWM (lighter area) immunostained for ET-1 by using the 3′3-diaminobenzidine tetrahydrochloride method. Blood vessel walls in the plaque and NAWM (red arrows) were positive for ET-1. Reactive astrocytes in the plaque (black arrows) were ET-1–positive, whereas astrocytes in NAWM were ET-1–negative (magnification of 2×).

Fig. 3.

Double immunostainings for ET-1 and GFAP. Representative photographs of tissue sections double-immunostained for GFAP (green, A and D) and ET-1 (red, B and E), visualized by confocal laser microscopy. (A–C) Cerebral white matter of a control. There was no colocalization between GFAP and ET-1 (C), indicating that normal astrocytes do not express ET-1. Blood vessels were ET-1–positive. (D–F) Chronic active MS plaque. ET-1 is present in reactive astrocytes (colocalization shown in yellow, F). (Scale bar: 50 µm.)

Fig. 4.

CBF in control subjects and in patients with MS before and 4 h after bosentan (†P = 0.02 and ¶P = 0.003, patients with MS at baseline vs. controls; §P < 0.001, patients with MS after bosentan vs. baseline).