Microvasculature, the Trigeminal System and Migraine

Aims of this thesis In Part I the focus is on experimental models of migraine, that are applied in pharmacological as well as in pathophysiological studies. Calcitonin gene-related peptide is the key neuropeptide in migraine pathophysiology. CGRP is being extensively researched, especially as a novel anti-migraine drug target. In Chapter 3 we review existing experimental models that can be applied to study the effects of the novel CGRP receptor antagonists and the recently developed antibodies directed against CGRP and its receptor. In Chapter 4 we comment on an existing experimental model to demonstrate its limitations with regard to distinguishing between structures important to migraine, like the intracranial part of the middle meningeal artery. In Chapter 5 we describe our experimental trigeminal nerve-mediated vasodilatation model. We developed this model to study trigeminovascular pathophysiological and pharmacological mechanisms of migraine. In Chapter 6 we investigate the effects of the anti-migraine drug sumatriptan with this model, to validate it as a biomarker for studies on future anti-migraine drugs. Besides its direct burden, migraine has recently also been identified as a major independent risk factor for cardiovascular disease. Yet, cross-sectional studies investigating the vascular dysfunction in migraine patients have reported conflicting results. This may relate to the fact that the experimental models used to identify vascular dysfunction were diverse and often limited. Therefore, in Chapter 7 we compared different measures of vascular function to assess their reproducibility and their usefulness to identify endothelial dysfunction. In Chapter 8 we applied one of these measures, the post-occlusive reactive hyperemia (PORH), to characterize the microvascular function in a knock-in mouse (V235fs KI mice) model of migraine. In Part II we evaluate the role of female sex hormones in migraine. The prevalence of migraine is much higher in women than in men. Hormonal milestones in women are