Migraine is a highly disabling neurovascular disorder characterized by a severe headache and activation of the trigeminovascular system, involving the release of the potent vasodilator calcitonin-gene related peptide (CGRP). Multiple drugs targeting the CGRP pathway have been developed for the acute and prophylactic treatment of migraine, including the monoclonal antibody erenumab and small molecule antagonists called gepants, which both target the CGRP receptor. Surprisingly, despite having the same target, gepants can exert additional effects on top of the monoclonal antibody erenumab in human isolated arteries. Moreover, gepants behave differently in human coronary arteries versus human middle meningeal arteries based on the slope of a Schild plot, and differential expression of subunits of the CGRP receptor family can be observed in the two vascular beds. Furthermore, activation of the CGRP receptor activates multiple intracellular signalling cascades, of which the expected second messenger cAMP, which is generally assumed to be the main signalling molecule, is not the main mediator of vasodilation. Instead, activation of Gβγ subunits results in relaxation of human coronary arteries. 

Interestingly, although CGRP receptor blockade seems an attractive target for the treatment of migraine, treatment is not effective in all migraine patients. Considering the complex pharmacology of CGRP signalling and blockade of its receptor, and its cardioprotective role during ischemia, more in depth analysis of patient-specific responses should be performed. We developed a vessel-on-chip model incorporating induced pluripotent stem cell (iPSC)-derived vascular smooth muscle cells and endothelial cells, allowing to study patient-specific blood vessels. Vascular responses of the cultured blood vessel model were compared to native human blood vessels, and similar responses to CGRP, adrenomedullin and adrenomedullin 2 could be observed in the model compared to human isolated blood vessels. Moreover, CGRP-induced increases in second messenger molecules in the vessel-on-chip model could be potently blocked using gepants, showing that the model can be used for pharmacological analyses. Endothelin-1 and angiotensin II, well-known vasoconstrictors, potently increased the intracellular calcium concentration of the 3D cultured blood vessels. This patient-specific blood vessel model can be used to further study the complex pharmacology of CGRP, and possibly aid in identifying the differences between responders and non-responders to this novel class, as well as future classes, of anti-migraine medication.