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Abstract

Background

Evidence of vascular dysfunction in migraine is increasing. MicroRNAs (miRs) have emerged as important regulators of vascular endothelial functions. This exploratory study investigated whether circulating levels of miRs associated with endothelial function are altered in migraine patients.

Methods

Thirty patients with migraine (20–50 years old) without overt vascular risk factors and 30 sex- and age-matched healthy controls participated. The levels of four miRs that regulate endothelial function (miR-155, miR-126, miR-21, and Let-7g) were quantified and expressed in terms of fold changes (2^−ΔΔct) relative to mean levels in the control group. Associations of miRs levels with headache features and syncope comorbidity were explored.

Results

Compared to controls, migraine patients had upregulated expression of miR-155 (6.17-fold, p = 0.018), miR-126 (6.17-fold, p = 0.013), and let-7g (7.37-fold, p = 0.005). Levels of miR-155 (r = 0.375, p = 0.041) and miR-126 (r = 0.375, p = 0.041) were associated with syncope frequency in the past year in migraine patients. Migraine patients with aura have insignificant higher expression of miRs levels compared to those without.

Conclusions

In this pilot study, circulating levels of endothelial-specific miRs appear to be elevated in migraine patients and may be associated with syncope comorbidity.

Keywords

Migraine microRNAs endothelial dysfunction syncope

Introduction

Migraine involves both vascular and neural mechanisms (1 –3). The impact of migraine on patient health may be further complicated by cardiovascular risk factors (4 –6) and syncope comorbidity (7,8).

Endothelial dysfunction has been documented both in patients with migraine (9 –12) and patients with syncope (13). Endothelial dysfunction refers to a dysregulation of endothelial cell functions, including poorly-controlled vascular tone and abnormal proliferative, migratory and morphogenic capacities (14). Compared to healthy controls, migraine patients have been reported to have decreased numbers and impaired functions of endothelial progenitor cells, including attenuated migratory capacity and increased senescence (10,11). Moreover, ultrasound studies have demonstrated multiple aspects of endothelial dysfunction in migraine patients, including flow-mediated vasodilation, breath-holding index (15), and vasomotor reactivity (16). A recent meta-analysis of genome-wide association studies of migraine patients revealed significant differences, relative to controls, within loci enriched with genes related to vascular development and healing (3). The discovery of specific endothelial dysfunction markers may enable clinical stratification of migraine patients according to their individual risk of cardiovascular comorbidity.

MicroRNAs (miRs) are short, non-coding RNAs that modulate gene expression post-transcriptionally (17). miRs that are abundently expressed in vascular cells can influence susceptibility to cardiovascular diseases and atherosclerosis by dampening the translation of key structural and regulatory protein targets, such as vascular cell adhesion protein 1 and tumor necrosis factor-α (17,18). Therefore, miRs that regulate endothelial function have the potential to serve as markers of vascular dysfunction (19).

Several miRs, including miR-155, miR-126, miR-21, and let-7g, have been shown to modulate inflammation and oxidative stress in endothelial cells and to regulate biochemical factors related to endothelial functions (20 –25). For example, miR-155, a key effector of endothelial inflammation and angiogenesis (14), is upregulated strongly and rapidly during neuroinflammation (26). In vascular injury or hypoxia status, miR-126 is upregulated markedly and plays a central role in tissue repair by inducing angiogenesis and endothelial remodeling (27). miR-21 is upregulated in injured dorsal root ganglion neurons in late-phase neuropathic pain (28) and its overexpression impairs angiogenesis (14). Expression of let-7g was found to be altered during endothelial cell senescence and inflammation (23). These miRs have never been explored in patients with migraine.

This exploratory study had two aims. First, we compared the levels of miRs implicated in endothelial functions, namely miR-155, miR-126, miR-21, and let-7g, in migraine patients with those in controls. Second, we explored whether levels of these miRs could be associated with particular headache profiles or syncope comorbidity.

Methods

Participants and protocol approval

The study protocol was approved by our hospital’s Institutional Review Board and written informed consent was obtained from each participant before entering the study. We recruited patients with episodic migraine with or without aura diagnosed by board-certified neurologists at the Headache Clinic at Taipei-Veterans General Hospital in accordance with the diagnostic criteria of the International Classification of Headache Disorders, 3rd edition, beta version (ICHD-3 beta) (29). Sex and age-matched healthy volunteers who did not have past or family histories of migraine, nor previous diagnosis of other primary or secondary headache disorders, except for infrequent episodic tension-type headaches (<1 day/month), were recruited from hospital and university staff as well as from the general population through advertisements.

Recruited patients underwent a detailed clinical interview and a neurological examination during their first visit to the clinic. Questionnaire-based interviews were carried out to collect demographic and clinical information, including: Disease duration of migraine; medication use; headache frequency, duration, intensity, location, quality, and triggers; and the presence of the six cardinal migrainous symptoms (i.e. unilateral pain, throbbing character, aggravation by or avoidance of physical activity, moderate or severe in intensity, “nausea or vomiting”, and “photophobia and phonophobia”). Patients were asked to report the average intensity of their headaches over the past 3 months on a Numeric Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable) (30). In addition, all patients had to fill in the Beck Depression Inventory to evaluate their depression symptoms (31).

The patients were also asked to report how often they experienced syncope (fainting) in the last year. Syncope was explained to the participants with verbiage of the Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA) study (8) as follows: A brief loss of consciousness that might be provoked by the sight of blood, directly after physical exertion (running, playing sports), while taking a long hot shower, or while standing in the heat for a long time, but that could also occur without a clear provocation. Loss of consciousness due to head injury or an epileptic seizure was excluded.

To eliminate potential confounding factors, the following exclusion criteria were applied to both migraine patients and controls: Age <20 years or >50 years; body mass index (BMI) <18 or >30 kg/m²; history of cardiovascular disease, hypertension, diabetes, hyperlipidemia, or stroke; heavy smoker (>20 cigarettes/day) (32); current pregnancy or lactation; infectious or inflammatory disease within a month prior to study commencement; major psychiatric disorder, such as major depression or bipolar disorders; or history of substance abuse. Patients with medication overuse headache (33), chronic migraine (34), or regular use of migraine preventive agents were also excluded. Subjects were asked not to use analgesics, non-steroidal anti-inflammatory agents, ergots, or triptans for at least 3 days before blood sampling. Eligible migraine patients were examined in the interictal period (≥24 hours headache-free).

Quantitation of miRs

Blood samples (5 mL) were collected in tubes containing ethylenediaminetetraacetic acid from migraine patients during a pain-free period and from healthy controls. The samples were centrifuged at 3000 rpm for 10 min and plasma was stored at −80℃ till analysis. Total RNA was extracted with a miRNeasy Serum/Plasma Kit (Qiagen, Germany) according to the manufacturer’s protocol (35). We then supplemented each sample with 1 nmol/uL Caenorhabditis elegans miR-39 (cel-miR-39) as a Spike-In Control (Qiagen, Germany) (36). Quantitative real-time polymerase chain reaction (PCR) was performed in an ABI 7900HT Fast Real-Time PCR system with TaqMan miRNA assays (Applied Biosystems, Foster City, CA) as described previously (23). Each miR expression level was calculated by the difference in threshold cycle method (ΔCt) (37) with normalization to cel-miR-39 (38). miR levels in interictal migraine patients were expressed by fold changes (2^−ΔΔct) relative to mean miR levels in the control group.

Intercellular adhesion molecule 1 (ICAM-1)

The level of ICAM-1, which is a marker of endothelial dysfunction involving endothelial inflammatory response and damage (25,44), was determined by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instruction using an EnSpire™ Multimode Plate Reader (PerkinElmer). The ELISA kit for ICAM-1 was purchased from R & D (Minneapolis, MN).

Statistical analysis

All statistical analyses were performed using SPSS version 22.0 (SPSS, Chicago, IL). We performed normality tests including Kolmogorov-Smirnov and Shapiro-Wilk tests for the miRs levels. The results showed the miRs level followed normal distributions for both tests. Mean values are reported with standard deviations (SDs). Continuous and categorical variables were compared between groups by Student’s t- and chi-squared tests as appropriate. Pearson correlation coefficients were calculated to detect associations between miR levels and headache profiles as well as comorbid syncope. Because the tested miR variables covaried with one another (correlation coefficients: 0.761–0.992), corrections for multiple comparisons were not applied to avoid false negative results. All tests were two-tailed and statistical significance was defined as p <0.05.

Results

Demographics and headache characteristics

The final sample consisted of 30 migraine patients and 30 age- and sex-matched healthy controls. Their demographic and clinical characteristics are summarized in Table 1.

Table 1.

Demographic and clinical characteristics of study participants (n = 30 for each group).

Characteristic	Migraine patients	Healthy controls	p
Age, mean (SD), y	35.3 (8.3)	34.6 (9.1)	.760
Female, no. (%)	22 (73.3)	22 (73.3)	>.999
Headache profile
Duration of migraine history, mean (SD), y	14.0 (4.8)	–	–
Frequency, mean (range), d/mo.	3.8 (2-8)	–	–
Intensity, mean (SD), NRS (0–10/10)	6.3 (1.4)	–	–
Migraine with aura, no. (%)	11 (37)	–	–
Scores of Beck Depression Inventory, mean (SD, range)	3.2 (2.6, 0-8)	–	–
Migrainous symptoms, no. (%)
Unilateral	24 (80)	–	–
Moderate to severe pain	28 (93)	–	–
Pulsatile quality	24 (80)	–	–
Exacerbation due to physical activities	26 (87)	–	–
Nausea or vomiting	24 (80)	–	–
Photophobia and phonophobia	16 (53)	–	–
Syncope ever, no. (%)	10 (33)	–	–
Mean no. of syncope in the last 12 months (range)	1.0 (0–8)	–	–
Acute attack treatment,* no. (%)
None	4 (13)	–	–
Triptans	1 (3)	–	–
Ergotamine with caffeine	4 (13)	–	–
Nonsteroidal anti-inflammatory drug	20 (67)	–	–
Acetaminophen with or without caffeine	21 (70)	–	–

Some patients used more than one type of abortive medication.

Levels of microRNAs

As demonstrated in Figure 1, miR-155, miR-126, and let-7g levels were 2- to 7-fold higher in the interictal migraine patients than in controls. A similar, but non-significant trend was observed for miR-21 (Figure 1).

Figure 1.

Comparisons of mean endothelial-specific miR levels between migraine patients and controls (n = 30 for each group). Error bars indicate ± one SD. All miR levels were demonstrated in fold changes (2^-ΔΔCt).

Correlation between microRNAs levels and clinical profiles

No miR expression level correlated with migraine patients’ headache features (Table 2). However, miR-126 levels were associated with the total number of cardinal migrainous symptoms (r = 0.374, p = 0.047) and both miR-155 (r = 0.375, p = 0.041) and miR-126 (r = 0.375, p = 0.041) levels were associated with the total number of syncope attacks in the past year in migraine patients. We also compared miR-126 levels across subgroups of migraine patients with each migrainous symptom versus those without. However, the results failed to show any significant differences (supplementary Table 1). Of note, migraine patients with aura had at least 2-fold higher, albeit statistically insignificant, expression of miR-155, miR-126, and Let-7g than those without (Table 3).

Table 2.

Pearson correlation coefficients (r values) of relationships between levels of endothelial-associated miRs and clinical profile variables.

	Migraine profile variable
miR	Duration of history, y	Headache frequency, d/month	Mean intensity, 0–10 scale	No. migrainous symptoms^a	No. syncope events in the past year
mi-R155	−0.071	−0.277	0.339	0.353	0.375 *
mi-R126	−0.096	−0.299	0.320	0.374 *	0.375 *
mi-R21	0.068	−0.197	0.266	0.322	0.222
let-7g	−0.053	−0.301	0.293	0.330	0.336

Cardinal migrainous symptoms: Unilateral pain; throbbing character; aggravated by or avoidance of physical activity, moderate/severe intensity, “nausea or vomiting”, and “photophobia and phonophobia”.

p < 0.05

Table 3.

Comparisons of mean (SD) endothelial-associated miR levels between migraine patients with aura (n = 11) versus without aura (n = 19).

Circulating miR	Migraine with aura	Migraine without aura	p
mi-R155	10.22 (11.80)	3.83 (7.59)	0.128
mi-R126	9.78 (11.41)	4.08 (6.91)	0.154
mi-R21	3.77 (6.77)	2.36 (4.23)	0.541
Let-7g	11.23 (11.33)	5.13 (8.75)	0.110

All miR levels determined by the 2^−ΔΔCt method.

Correlations between microRNAs levels and ICAM-1 level

We investigated the associations between levels of miRs and the level of ICAM-1 as a marker of endothelial dysfunction. We found that, except for miR-126, the levels of miR-155, miR-21 and Let-7g were positively associated with the level of ICAM-1 (r = 0.376, p = 0.040; r = 0.412, p = 0.024; r = 0.377, p = 0.040) in migraine patients.

Discussion

In this exploratory study, we observed multi-fold higher circulating blood levels of miR-155, miR-126, and Let-7g in patients with migraine than in healthy controls. Furthermore, miR-155 and miR-126 levels correlated with syncopal attack frequency in migraine patients. In addition, we also demonstrated that the levels of miR-155, miR-21 and Let-7g in migraine patients were positively associated with the level of ICAM-1, a marker of endothelial dysfunction (25,44).

There are only a few miRs studies on patients with migraine (36,39,40). One case-control study comparing 24 migraine patients and 24 age- and sex-matched controls showed an association between migraine attacks and acute upregulation of the GABAergic-related miRs, such as miR-34a-5p and miR-382-5p (36). Interestingly, miR-382-5p exhibited an upregulation during both attacks and pain-free periods and was suggested to be a biomarker for migraine (36). However, no attempt was made to differentiate miRs expression between patients with migraine without aura and those with aura in this study. Another recent study investigating 15 female patients with migraine without aura during pain-free periods and 13 matched controls showed that migraine without aura was associated with modulation of atherosclerosis-related miRs, including miR-181a, let-7b, miR-27b, and miR-22 (39). Since the sensitivity and specificity of the four miRs were highly comparable to the migraine diagnosis in this study, the authors suggested that the concomitant evaluations of these four miRs might be used to diagnose migraine, although further large-scaled studies are required for confirmation. Our study was based on endothelial dysfunction reported in migraine patients (11,12). We selected specific miRs as targeted markers and evaluated the expression during pain-free periods using threshold cycle method (ΔCt) as in previous research (23). As reported in supplementary Table 2, the intra-assay coefficients of variation derived from duplicate data of qRT-PCR reactions reflected qualified experimental procedures. Of note, transforming growth factor beta receptor 2 (TGFBR2), recently identified as a susceptible gene in migraine patients (3), was found to be targeted by miR-155 (41), which was found to have elevated expression in migraine patients in the present study.

Our findings support the notion that migraine and vascular events may be assocaited with endothelial dysfunction (9,10). In addition, our findings of correlations of endothelial-specific miR levels with syncopal frequency in migraine patients is consistent with a mechanistic commonality between migraine and syncope and supports the suggestion that migraine may be a risk factor for syncope (8).

Regarding cardiovascular event risk, a previous study showed that female migraine patients with aura were at an elevated risk of developing cardiovascular events (42). Although expression levels of three of the examined miRs in our migraine patients with aura were more than double that in migraine patients without aura, the comparisons were not significant, likely due to insufficient power. Nevertheless, our findings might extend the results from a previous cohort study (4) indicating a link between migraine and cardiovascular disease events.

This study has limitations. First, the study design did not allow for delineation of the cellular origin of circulating miRs, and as such, it cannot be determined which structures are responsible for their release. Second, we studied a relatively homogenous group of healthy adults with episodic migraine without known cardiovascular risk factors. Thus, it is not known how well our findings would be generalized to populations with comorbidities or cardiovascular risk factors, older patients, or patients with chronic migraine. Third, we did not compile systematic data on the related confounders which may have had an impact on the miRs expression. These confounders may include different phases of menstrual cycle when patients’ blood samples were taken and other comorbidities, such as fibromyalgia, since the latter is associated with syncope (43). Fourth, this study is exploratory in nature and is underpowered to demonstrate associations between miR level and a specific headache profile, such as migraine aura. Fifth, although all the qRT-PCR experiments were conducted by one experienced operator, unfortunately we did not perform measurements testing the intra-observer correlations because of the precious and limited plasma sample from each study subject. Last but not least, in this pilot study, except for ICAM-1 level, we did not perform other parameters associated with endothelial dysfunction, such as flow-mediated dilation, levels of endothelin-3 or epithelial progenitor cells. Based on our preliminary results, further studies to include a large sample size and more parameters related to endothelial dysfunction are needed to confirm our results.

Conclusions

In this pilot study, we demonstrated that levels of endothelial function-related miRs were altered in patients with migraine during interictal periods. Our findings may shed light on understanding the mechanism mediating endothelial dysfunction in migraine and suggest that quantification of targeted miRs, such as those examined here, could be used for stratification of cardiovascular risks in migraine patients. Further large-scale research is needed to confirm our results.

Clinical implications

We observed 2- to 7-fold higher expression of endothelial dysfunction-associated miRs in patients with migraine than in controls.

miR-155 and miR-126 levels correlated with syncopal attack frequency in migraine patients.

Our findings suggest the notion of a link between migraine and cardiovascular risk.

Specific miR quantification in migraine patients may be used to predict the cardiovascular risk.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported in part by grants from Taipei Veterans General Hospital [VGHUST105-G7-1-1, V105C-127, V105E9-001-MY2-1, VTA105-V1-1-1, V106D21-003-MY2-1]; the Ministry of Science and Technology of Taiwan [MOST 104-2314-B-010-015-MY2, MOST 103-2628-B-075-001-MY3 and MOST 103-2321-B-010-017-]; the Ministry of Science and Technology support for the Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan [MOST 103-2911-I-008-001]; Academia Sinica [Grant No. IBMS-CRC103-P04]; and the Brain Research Center at National Yang-Ming University, Ministry of Health and Welfare, Taiwan [MOHW 103-TDU-B-211-113-003, MOHW 104-TDU-B-211-113-003, MOHW 105-TDU-B-211-113-003], as well as a grant from the Ministry of Education, Aim for the Top University Plan. The opinions, results, and conclusions reported in this article are those of the authors and were developed independent of the funding sources.

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Supplementary Material

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Elevated circulating endothelial-specific microRNAs in migraine patients: A pilot study

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Participants and protocol approval

Quantitation of miRs

Intercellular adhesion molecule 1 (ICAM-1)

Statistical analysis

Results

Demographics and headache characteristics

Levels of microRNAs

Correlation between microRNAs levels and clinical profiles

Correlations between microRNAs levels and ICAM-1 level

Discussion

Conclusions

Clinical implications

Footnotes

Declaration of conflicting interests

Funding

References

Supplementary Material