Circulating microparticles in migraine with aura: cause or consequence, a link to stroke.

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 migraineassociated 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