The many studies assessing endothelial function in migraineurs have used heterogeneous techniques and indicators as shown in Tables  2, 3 and 4. Most of them assessed endothelial function by measuring FMD (Table  2) 20 21 22 23 24 25 26 27 28 29 30 , some used PAT (Table  3) 31 32 , some measured peripheral vasodilation in response to pharmacological stimuli (Table  3) 20 30 33 34 35 , and others assessed endothelial progenitor cells (EPCs) (Table  4) 23 36 37 . Findings were not consistent across the studies. Several among the available studies did not reveal any alteration in the endothelial function of migraineurs. Six of them did not find any difference in FMD between migraineurs and control subjects (Table  2) 20 21 22 23 25 26 and a further study confirmed the lack of any alteration in endothelial function assessed by PAT ratio (Table  3) 32 . Three studies assessing peripheral vasodilation after pharmacological stimuli found comparable responses in subjects with and without migraine (Table  3) 20 33 35 . However, other studies supported the presence of endothelial dysfunction in migraineurs. Four studies reported decreased FMD in migraineurs 24 27 29 30 ; in one of those studies, FMD correlated with dysfunction of the autonomic nervous system (Table  2) 24 . Another study, using PAT, reported that subjects with chronic migraine had worse endothelial function (Table  3) 31 . A further study found an abnormal vascular response to dilating pharmacological stimuli (Table  3) 34 . The possible underlying mechanisms of endothelial dysfunction in those studies were unclear. Since the impairment of FMD was demonstrated also in individuals with recent onset of migraine it is unlikely that the disturbance was a consequence of longstanding and repeated exposure to the vasoconstrictor agents used for migraine treatment 27 . In addition, the results of one study suggested that the impaired vascular reactivity in migraineurs is entirely attributable to a reduced response of vascular smooth muscle cells to NO while the endothelial response to NO appeared intact 34 . Some additional studies supported the presence of an endothelial dysfunction in migraineurs by documenting a decreased number of EPCs 23 36 or a higher number of more mature EPCs (which could be associated with potential endothelial damage) in migraineurs (Table  4) 37 . EPCs maintain the integrity of damaged endothelium and are considered a marker of endothelial function 38 . At variance with other studies, Vernieri et al., found that subjects with migraine with aura had higher FMD than both control subjects and migraine without aura subjects indicating an excessive arterial response to hyperemia. It is suggested that this is probably an effect of an increased sensitivity to endothelium-derived NO or of increased release of NO induced by shear stress (Table  2) 28 . In agreement, Yetkin et al., found that migraineurs have an increased nitrate-mediated response showing a major role of NO supersensitivity in migraine pathophysiology (Table  3) 30 .

CC case–control; MwA migraine with aura; MwoA migraine without aura; CVD cardiovascular disease; HYP arterial hypertension; DM diabetes mellitus; CS cigarette smoking; RF risk factors; FANS non steroid anti-inflammatory drugs; OC oral contraceptives; CAD coronary artery disease; ICHD International classification headache disorders; FMD flow-mediated dilation.

CC case–control; CM chronic migraine; MwA migraine with aura; MwoA migraine without aura; CVD cardiovascular disease; HYP arterial hypertension; DM,diabtes mellitus; CS cigarette smoking; OC oral contraceptive; ICHD International classification headache disorders; RHI reactive hyperhemia index; PAT peripheral arterial tonometry; CGRP Calcitonin Gene Related Peptide; cGMP cyclic guanosine monophosphate; NO nitric oxide.

CC case–control; CM chronic migraine; EM episodic migraine; MwA migraine with aura; MwoA migraine without aura; CVD cardiovascular disease; CAD coronary artery disease; HYP arterial hypertension; DM diabetes mellitus; CS cigarette smoking; ICHD International classification headache disorders.

Several studies support the presence of biochemical changes in the endothelial activation of migraineurs. These biochemical changes may precede structural damage. In particular, alterations in the NO pathway have been described 30 39 40 as well as increased levels of calcitonin gene-related peptide (CGRP), vascular endothelial growth factors (VEGF), von Willebrand factor (vWF) activity, tissue plasminogen activator antigen, C-reactive protein and endothelin-1 21 23 40 . Recently, a study involving 40 non-hypertensive subjects with migraine without aura randomized to treatment with enalapril 5 mg twice a day for 3 months or to placebo, showed that active treatment was associated with an increase in FMD values 41 .

Compared with studies on endothelial function, reports on arterial function measured with PWV, AIx, and local arterial distensibility are more consistent and suggest that functional properties of large arteries are altered in migraineurs 27 42 43 44 45 46 (Table  5).

CC case–control; PB population-based; CM chronic migraine; MwA, migraine with aura; MwoA, migraine without aura; CVD, cardiovascular disease; HYP, arterial hypertension; DM, diabetes mellitus; RF, risk factors; ICHD, International classification headache disorders; AIx, augmentation index; PWV, pulse wave velocity.

Four studies addressed PWV in migraineurs (Table  5) 27 42 43 44 . Ikeda et al. evaluated peripheral PWV 42 while the other authors assessed central PWV 27 43 44 . Three studies on PWV 27 42 43 found higher values of this parameter in migraineurs with respect to non-migraineurs. However, in one of the studies PWV did not correlate with the presence of migraine after adjustment for age and mean arterial pressure 27 . The inclusion in the study of patients with a short history of migraine and with less use of vasoconstrictive agents may explain the difference 27 . Schillaci et al., also addressed PWV according to migraine type and reported that subjects with migraine either with or without aura had increased PWV with respect to controls while migraine with aura subjects had higher aortic PWV than those without aura 43 . A more recent population-based study, involving a larger number of migraineurs, has challenged the suggestion of possible impairment of arterial function in migraineurs 44 . In fact, Stam et al. reported no differences in PWV among subjects with migraine with aura, migraine without aura, and controls 44 . In this latter study subjects with known cardiovascular risk factors were included and this may explain the differences in the results 44 .

Higher values of AIx were found in migraineurs by five studies 27 31 32 43 45 , which variously measured AIx in the radial artery 45 , in the aorta 27 43 or by finger tonometry 31 32 . One of those studies involved only women with migraine with aura 32 and one involved only subjects with chronic migraine 31 . Schillaci et al. reported increased AI in migraine with and without aura with respect to controls and no differences between the two groups of migraineurs 43 . All the studies about AIx had a case–control design, except for a population-based one 45 which involved cases and controls older than those of the other studies.

Two studies assessed static arterial parameters 27 46 . De Hoon et al. found that migraineurs had larger temporal artery diameter compared with control subjects but a decreased distensibility and buffering capacity of the brachial artery in the absence of significant alterations in the common carotid and femoral arteries 46 . Vanmolkot et al. found that migraineurs had a decreased diameter and compliance of superficial muscular arteries 27 .