Abstract
Over the past three decades, epidemiological studies have firmly established migraine with aura as an important risk factor for ischemic stroke, particularly in young women (1), and those without conventional cardiovascular risk profiles (2). The discovery of migraine’s association with a number of other vascular conditions such as Raynaud’s phenomenon (3), variant angina (4), pre-eclampsia (5), and livedo reticularis (6), has fueled speculation for a pivotal role of the endothelium in migraine pathogenesis and in migraine-associated stroke (7).
The endothelium is an active endocrine organ, producing substances to maintain vascular and neural homeostasis (e.g. prostacyclin, endothelin-1, angiotensin II, and nitric oxide), while inactivating other vasoactive substances (e.g. serotonin and bradykinin). Endothelial dysfunction (ED) is characterized by impaired vascular reactivity and by endothelial activation. In migraine, reactivity studies have mostly focused on the peripheral vasculature, and findings are conflicting (8). Evidence of increased arterial stiffness, however, has been more uniform (9–12). Findings of a pro-inflammatory and procoagulatory milieu in migraine have been offered as indirect evidence of endothelial activation (13). Newer lines of investigation include the quantification of circulating endothelial progenitor cells, and each of three studies has demonstrated significant differences (either increased or decreased) between migraineurs and the control group (14–16). This has been interpreted as being related to increased need for endothelial repair.
In their article “Circulating endothelial microparticles in female migraineurs with aura,” Liman and coauthors report a case-control study of a novel surrogate marker for endothelial activation in a small cohort of premenopausal women, the subgroup at highest risk of stroke (17). Microparticles (MPs) is the term for the submicron membrane vesicles released from different cell populations into the circulation in response to various stimuli (18). Although initially referred to as “cellular debris,” it is now recognized that the quality and quantity of circulating MPs carry a wealth of biological information (18,19). The specific protein and oxidized phospholipid composition of the MPs reveals both the cellular origin (e.g. platelets, monocytes, endothelial cells) as well as the underlying stimulus producing them (e.g. activation, injury, apoptosis). It is estimated that at least 70% of circulating MPs are derived from platelets with only 5% to 15% from endothelial cells (19). The quantity of MPs in the circulation increases across the spectrum from health to disease.
The main finding from the study by Liman et al. (17) is that levels of endothelial MPs (EMPs) related to endothelial activation are elevated in young women with migraine with aura. Furthermore, the activated EMP levels positively correlate with the finger tonometry-derived augmentation index, a marker of arterial stiffness. Lastly, the authors report that levels of MPs from platelets (PMPs) and monocytes (MMPs) are also elevated in migraine, indicating a pro-inflammatory and hypercoagulable state.
The implications of these findings as they pertain to migraine pathogenesis and stroke risk are best understood in the context of the literature. Cell culture studies demonstrate that EMPs are shed on exposure to inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF) alpha (18,19). Levels of these and other cytokines are elevated in the plasma of migraineurs between attacks (compared to healthy controls), and rise during attacks (compared to their interictal levels) (20–24). Interictal cytokine levels have been reported to correlate with migraine frequency (22). These data suggest that the endothelium is activated as a consequence of migraine, with EMPs as a biomarker of this activation, and the constellation of physiological events generated by aura promotes inflammation and coagulation, as evidenced by levels of PMPs and MMPs. Other evidence supporting the contention that migraine affects the endothelium come from animal studies showing that recurrent cortical spreading depression (CSD) (25), the physiological correlate of migraine aura, leads to a decrease in vascular reactivity (26). In addition to being a biomarker of endothelial activation, there is also evidence that EMPs are agents in the development of endothelial dysfunction (18,19). EMPs inhibit endothelial nitric oxide synthase, leading to decreased capacity for vasodilation, and, as was demonstrated by Liman et al. (17), increasing systemic arterial stiffness. By triggering endothelial release of chemokines and attracting leukocytes to the endothelial surface, EMPs may also play a vital role in promoting inflammation and thrombosis (18). Coming full circle, thromboembolic-related cortical ischemia has been proposed as a possible mechanism of migraine with aura (27). Other evidence that biological changes resulting from endothelial dysfunction may lead to migraine include 1) decreased nitric oxide increases susceptibility to CSD (28), 2) cortical application of endothelin-1, a potent endothelial vasoconstrictor and ED mediator, induces CSD (29), 3) genetic polymorphisms associated with ED are likewise associated with migraine (30,31), and 4) pharmacologic agents that improve endothelial function, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, also prevent migraine (32,33).
This exploratory study is small and doesn’t include people with migraine without aura, nor does it include men and older individuals. Frequency, duration, and severity of migraine are not factored into the analysis. No data are presented on the presence of magnetic resonance imaging (MRI) white matter changes or of patent foramen ovale, both highly prevalent in this subset of migraineurs. As a cross-sectional study, the exact nature of the migraine-endothelial link remains elusive. It is nevertheless an exciting step forward in improving our understanding of migraine and its relationship to stroke. Since circulating MPs have been tied to increased risk of ischemic events, they may allow for the identification of migraineurs at increased risk of stroke and other vascular disease. These findings also open new avenues of research on therapeutic targets for prevention of migraine and stroke.
Footnotes
Conflict of interest
None declared.