The Role of Renin-Angiotensin System in the Pathophysiology of Migraine

One woman who is stressed or in pain from depression, anxiety or headache related health issues
While it does not influence migraine severity, the renin-angiotensin system (RAS) has an important role in the pathophysiology of migraine.

While it does not influence migraine severity, the renin-angiotensin system (RAS) has an important role in the pathophysiology of migraine. Serum levels of angiotensin converting enzyme (ACE) are lower and those of angiotensin II and angiotensin (1-7) levels are higher in patients with migraine than in controls, according to study results published in Headache.

Although migraine is very common, the pathophysiology of migraine is not fully understood. Recent studies suggested that drugs that interfere with the RAS may be useful to prevent migraine. As limited data exist on the role of RAS in migraine, the current study aimed to investigate the serum levels of RAS markers in patients with migraine and its association with migraine severity.

This cross sectional study included adults aged between 18 and 60 years with episodic migraine. The Headache Impact Test, version 6 (HIT-6) questionnaire, and Migraine Disability Test (MIDAS) questionnaire were used to assess headache impact. The Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI), respectively, were used to assess anxious and depressive symptoms. Blood was collected to determine serum levels of ACE, ACE2, angiotensin II, and angiotensin (1-7).

The study sample included 30 (mean age, 29 years) patients with episodic migraine and 20 (mean age, 29 years) healthy controls from the outpatient clinic at Hospital das Clinicas (Universidade Federa de Minas Gerais, Belo Horizone, Brazil). Patients with migraine and controls were comparable in body mass index, blood pressure, and BDI and BAI scores.

The average HIT-6 score was 62.9 and the median MIDAS score was 23.5. Among patients with migraine, ACE levels (65.5vs 85.2, respectively; P =.005) and ACE/ACE2 ratio (3.5 vs 4.3, respectively; P =.032) were lower, compared with those in healthy controls. Conversely, levels of angiotensin II (605.4 vs 309.7, respectively; P <.001) and angiotensin (1-7) (397.9 vs 214.4, respectively; P =.001) levels were higher in patients with migraine, compared with controls.  There were no differences in levels of ACE2 or in angiotensin-II/angiotensin (1-7) ratio between the groups.

Study researchers observed no correlation between RAS serum markers and migraine severity according to HIT or MIDAS questionnaires. They also observed no correlation between RAS serum markers and depressive or anxious symptoms, according to BDI and BAI scores, respectively.

The study had several limitations, including the relatively small sample size, cross-sectional design, potential enrollment bias, and limiting the study sample to patients with episodic migraine not taking any prophylactic treatment.

The study researchers concluded that their “results suggest the participation of RAS in migraine pathophysiology, but not in its severity,” and that further longitudinal studies are needed “to establish the influence of the RAS markers on migraine development and headache attacks.”


Martins LB, Silva de Miranda A, Rodrigues AMDS, et al. Altered serum levels of renin-angiotensin system markers in migraine. Headache. Published online September 2, 2020. doi:10.1111/head.13949