Neurovascular contributions to migraine: Moving beyond vasodilation

Abstract

Migraine is the third most common disease worldwide, the most common neurological disorder, and one of the most common pain conditions. Despite its prevalence, the basic physiology and underlying mechanisms contributing to the development of migraine are still poorly understood and development of new therapeutic targets is long overdue. Until recently, the major contributing pathophysiological event thought to initiate migraine was cerebral and meningeal arterial vasodilation. However, the role of vasodilation in migraine is unclear and recent findings challenge its necessity. While vasodilation itself may not contribute to migraine, it remains possible that vessels play a role in migraine pathophysiology in the absence of vasodilation. Blood vessels consist of a variety of cell types that both release and respond to numerous mediators including growth factors, cytokines, adenosine triphosphate (ATP), and nitric oxide (NO). Many of these mediators have actions on neurons that can contribute to migraine. Conversely, neurons release factors such as norepinephrine and calcitonin gene-related peptide (CGRP) that act on cells native to blood vessels. Both normal and pathological events occurring within and between vascular cells could thus mediate bi-directional communication between vessels and the nervous system, without the need for changes in vascular tone. This review will discuss the potential contribution of the vasculature, specifically endothelial cells, to current neuronal mechanisms hypothesized to play a role in migraine. Hypothalamic activity, cortical spreading depression (CSD), and dural afferent input from the cranial meninges will be reviewed with a focus on how these mechanisms can influence or be impacted by blood vessels. Together, the data discussed will provide a framework by which vessels can be viewed as important potential contributors to migraine pathophysiology, even in light of the current uncertainty over the role of vasodilation in this disorder.

Keywords: cortical spreading depression; endothelial cells; hypothalamus; meningeal afferents; migraine; vasodilation.

Fig. 1

Anatomy of a blood vessel. Bloods vessels are comprised of 3 layers: the tunica intima, tunica media, and tunica adventitia. The innermost layer, the tunica intima, is comprised of a single layer of endothelial cells. The middle layer, the tunica media is predominately comprised of smooth muscle cells. The outermost layer, the tunica adventitia, consists of nerve fibers, fibroblasts, perivascular adipose tissue and collagen. Compared to smaller vessels (as depicted here), large vessels have increased tunica intima/media/adventitia thick- ness due to increased numbers of cells in each layer.

Fig. 2

Bidirectional signaling between meningeal nerve fibers, immune cells and cells comprising the associated blood vessels. Meningeal sensory afferents originating from the trigeminal ganglia innervate the meningeal vasculature and release vasoactive neuropeptides including substance P (Sub P) and calcitonin gene- related peptide (CGRP). In addition, sympathetic efferents from the superior cervical ganglion release neurotransmitters including neu- ropeptide Y (NPY) and norepinephrine (NE) that can act on vessels in the meninges. Conversely, cells comprising the blood vessel as well as those in the vascular lumen can influence meningeal sensory afferents. Endothelial cells can release c-type natriuretic peptide (CNP) and potentiate sensory afferent neuronal firing. During angio- genesis, endothelial cells release vascular endothelial cell growth factor (VEGF), which recruits immune cells such as macrophages and neutrophils. The recruited immune cells infiltrate the nearby tissue and release cytokines known to sensitize sensory afferents. In addition, changes in metabolic demand and other stimuli such as shear stress can cause the release of adenosine triphosphate (ATP) from multiple cell types within the vessel. Endothelial cell purinergic receptor activation causes the release and diffusion of nitric oxide (NO) throughout the vessel and surrounding tissue resulting in a wide range of effects including sensory afferent sensitization.