The Role of Endothelial Dysfunction in the Pathophysiology and Cerebrovascular Effects of Migraine: A Narrative Review

Abstract

Background and Purpose Migraine is a complex neurovascular disorder whose triggers are not entirely understood. Endothelial dysfunction might play a role in migraine, and there have been numerous reports on endothelium dysfunction and migraine pathophysiology, but their reciprocal cause–effect relationship remains unclear. This review reports the current evidence on endothelium dysfunction, its link with migraine, and its possible consequences for cerebral hemodynamics. Methods We performed a systematic literature search of PubMed up to March 2020. We included 115 articles in a narrative review. Results Several studies have demonstrated that endothelium dysfunction may play an important role in migraine. Despite the lack of specific biomarkers, there is evidence of oxidative stress and inflammation—two of the primary causes of endothelial damage—in migraine. The main consequences of endothelial dysfunction are increased vascular tone, thrombosis, inflammation, and increased vascular permeability. As a consequence of oxidative stress, the activity of endothelin-1 is not counterbalanced by nitric oxide (NO), whose levels decrease to lead to vasoconstriction and a possible contribution to cortical spreading depression. NO is involved in pain perception via the cyclic guanosine monophosphate (cGMP) pathway and the induction of calcitonin gene-related peptide. Oxidative stress may induce a hypercoagulable state that mainly affects platelet function through different mechanisms. Endothelial dysfunction seems to be particularly pronounced in migraine with aura (MA). Endothelial dysfunction in migraine particularly involves intracranial vessels, since flow-mediated dilation cannot detect overt peripheral vascular dysfunction. Conclusions Endothelial dysfunction is a vascular risk marker. How it impacts migraine, and particularly MA, needs to be understood better by defining its possible role in increasing the stroke risk in migraine patients.

Migraine Aura, Transient Ischemic Attacks, Stroke, and Dying of the Brain Share the Same Key Pathophysiological Process in Neurons Driven by Gibbs–Donnan Forces, Namely Spreading Depolarization

“…However, with respect to migraine aura, this traditional controversy between the vascular and neuronal theory dissolved when it became clear that epipial, i.e., abluminal, application of the vasoconstrictor polypeptide endothelin-1 is currently the most potent trigger of spreading depolarization in rodents in vivo and that endothelin-1 has this effect because of its vasoconstrictor properties, causing an imbalance between energy supply and demand of neurons (Dreier et al, 2002a). These findings have contributed significantly to the hypothesis that endothelial dysfunction could be one of the different etiologies leading to spreading depolarization and migraine aura in certain circumstances (Kleeberg et al, 2004;Dreier et al, 2007;Ducros, 2012;Dreier and Reiffurth, 2015;Liman et al, 2015;Oliveira-Ferreira et al, 2020;Paolucci et al, 2021). In recent clinical studies, intravenous infusion of endothelin-1 induced aura symptoms neither in healthy volunteers nor in patients with a history of migraine aura (Hougaard et al, 2020a,b).…”

Effect of caffeine and caffeine cessation on cerebrovascular reactivity in patients with migraine

“…Although it is unclear whether caffeine is beneficial to systemic endothelial function, cerebral endothelial function, particularly CVR, differs from systemic endothelial function, at least in patients with migraine 18 . Cerebral circulation is different from systemic circulation as it is under complex control of neural, chemical, myogenic, and autonomic factors 22,24,30,41 . Caffeine can affect cerebral circulation through neural, chemical, and autonomic pathways as it is a neurostimulant as well as an adenosine receptor antagonist, and it can increase sympathetic nervous activity 42 .…”

“…We did not collect data regarding test reliability, but previous studies showed acceptable within‐day reliability of TCD BHI 29 . Based on previous studies, we selected MCA and PCA to represent anterior and posterior cerebral circulation 21,22 …”

“…CVR is usually reduced in migraine, particularly in the posterior circulation 16–18 . However, conflicting results also exist, 19,20 and the results vary depending on the vascular distribution and presence of aura 21,22 . A recent meta‐analysis concluded CVR is reduced in the posterior circulation in patients with migraine, particularly in patients with migraine without aura (MWoA), but the heterogeneity among studies was quite high 23–25 …”

Covert Brain Infarcts in Patients with Philadelphia Chromosome-Negative Myeloproliferative Disorders

“…It has been previously shown that endothelial dysfunction is common among patients with MPD, especially with thrombotic events [ 23 , 24 ]. FMD is a functional way to assess NO-mediated endothelial function; it involves measuring brachial artery dilation following a transient (≈5 min) period of forearm ischemia [ 25 ]. Lower FMD values are associated with endothelial dysfunction.…”