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.

Keywords: hypercoagulability; inflammation; thrombosis; vasoconstriction; vasodilatation.

Fig. 1. Proposed mechanism of endothelial dysfunction in migraine pathophysiology. Oxidative stress and other endogenous and exogenous factors may lead to endothelium dysfunction, consequently sustaining the induction of pain and possibly increasing the vascular risk via alterations of vascular tone and hypercoagulability. ATP: adenosine triphosphate, cAMP: cyclic adenosine monophosphate, cGMP: cyclic guanosine monophosphate, cGRP: calcitonin-gene-related peptide, CLDN5: claudin-5, CRP: C-reactive protein, CSD: cortical spreading depression, eNOS: endothelial nitric oxide synthase, ESM-1: endocan, ET-1: endothelin-1, IL-1β: interleukin 1β, IL-6: interleukin 6, nNOS: neuronal nitric oxide synthase, NO: nitric oxide, TNF-α: tumor necrosis factor-α, SP: substance P, vWF: von Willebrand factor, 5HT: serotonin.

Fig. 2. Damage and loss of stability of endothelium lead to the release of endothelial microparticles (EMPs). ARE: arylesterase, EPCs: endothelial progenitor cells, ox-LDL: oxidized low-density lipoprotein, PON-1: paraoxonase-1, SDF-1α: stromal-cell-derived factor-1α.

Fig. 3. Cerebrovascular reactivity (CVR) studies adopting breath-holding or L-arginine infusion in migraine with aura (MA) patients compared with controls. Data were extracted from the meta-analysis of Dzator et al. ADMA: asymmetric dimethylarginine, BP: blood pressure, EtCO2: end-tidal CO₂, L-arg: L-arginine, NOS: nitric oxide synthase, RLS: right-to-left shunt, SDMA: symmetric dimethylarginine.