Relevance of mouse vasculature in investigating side-effects of anti-migraine medications.

Abstract text (incl. figure legends and references)

Objective

The gold standard treatment in migraine, the triptans, are usually not prescribed to patients with cardiovascular risk factors. Further it has been debated whether, the Gepants and anti-CGRP/CGRP receptor antibodies (collectible named anti-CGRP treatments) poses an additional risk in patients in relation to cardiovascular disease. There are some studies aiming to address this experimentally, particular using mice models. We therefore set out to investigate if the mouse is a good model for cardiovascular effects of anti-migraine treatments.

Methods

∼2mm long isolated mouse coronary (40µm wire) and basilar segments (25 µm wire) were mounted on a Mulvany–Halpern myograph. The smooth muscle cell contractile function was confirmed by challenging the segments two times with K+. We performed a concentration response curve to 5-HT with a maximal concentration of 10 µM. Following an addition of U46619 (~ 0.1 µM), the segments where challenged with CGRP (1 µM) followed by PACAP (0.1 µM).

Results

Mouse coronary arteries contracted to 5-HT (110 ± 13% of the K+), and receptor characterization showed that the 5-HT2A receptor was responsible for the contraction. To ensure visible dilation, we used minimal precontraction for the coronary arteries (62 ± 4.9 % of K+) and basilar arteries (19 ± 6.1 % of K+). The coronary arteries dilated to CGRP (50 ± 7.8 %) but not to PACAP (-6 ± 2.7%). These results contrast to the basilar artery, which did not significantly contract to 5-HT (5.4 ± 1.8%, p=0.06). More important, the basilar artery did not dilate in response to CGRP (9±12%. P=0.46), whereas PACAP had a significant dilatory response (49 ± 4.4%. P=0.002).

Conclusion

These data show that using the mouse as a model organism for side effects of anti-CGRP treatments should be analyzed with care, as the arteries do not have similar expression profile as human arteries. In relation to migraine, it is interesting that cerebral arteries appear to lack CGRP receptors in mice.