Opposite Reactivity of Meningeal versus Cortical Microvessels to the Nitric Oxide Donor Glyceryl Trinitrate Evaluated In Vivo with Two-Photon Imaging

Abstract

Vascular changes underlying headache in migraine patients induced by Glyceryl trinitrate (GTN) were previously studied with various imaging techniques. Despite the long history of medical and experimental use of GTN, its effects on the brain vasculature are still poorly understood presumably due to low spatial resolution of the imaging modalities used so far. We took advantage of the micrometer-scale vertical resolution of two-photon microscopy to differentiate between the vasodynamic effects of GTN on meningeal versus cortical vessels imaged simultaneously in anesthetized rats through either thinned skull or glass-sealed cranial window. Intermediate and small calibre vessels were visualized in vivo by imaging intravascular fluorescent dextran, and detection of blood flow direction allowed identification of individual arterioles and venules. We found that i.p.-injected GTN induced a transient constriction of meningeal arterioles, while their cortical counterparts were, in contrast, dilated. These opposing effects of GTN were restricted to arterioles, whereas the effects on venules were insignificant. Interestingly, the NO synthase inhibitor L-NAME did not affect the diameter of meningeal vessels but induced a constriction of cortical vessels. The different cellular environment in cortex versus meninges as well as distinct vessel wall anatomical features probably play crucial role in the observed phenomena. These findings highlight differential region- and vessel-type-specific effects of GTN on cranial vessels, and may implicate new vascular mechanisms of NO-mediated primary headaches.

Targeted Nitric Oxide Synthase Inhibitors for Migraine

“…Chronic intermittent treatment with NTG has also been found to evoke a long-lasting basal hypersensitivity, which is sensitive to migraine preventives [32,33], thus serving as a behavioral model of chronic migraine. NTG can also evoke other migraine-related physiological effects, and has been shown to produce light-aversion [34,35] and changes in the cranial vasculature of rodents [34,36,37]. Taken together, these results strengthen the notion of increased NO as a hallmark of migraine-associated symptoms, and establishes NTG as a useful translationally significant model of migraine.…”

Estrogen-Dependent Changes in Dura Mater Microvasculature Add New Insights to the Pathogenesis of Headache

“…Similar to the brain, cranial dura mater is situated inside the intracranial cavity, an indistensible closed space uniquely sensitive to changes in pressure, and a chemically privileged site ( 18 ). As Strassman and Levy ( 18 ) point out, “The distinctive clinical characteristics of headache may prove to be related not so much to any differences in the intrinsic molecular or cellular properties of the meningeal sensory neurons but rather to the distinctive properties of the tissue that they innervate,” which is consistent with recent findings showing that the very same treatment with the migraine trigger glyceryl trinitrate can simultaneously induce opposite reactions: vasoconstriction in meningeal and vasodylation in cortical microvasculature ( 6 ). Thus, different physiological or pathological processes within the intracranial dura, most heavily innervated by nociceptive afferents, will certainly affect meningeal sensory neuron activity.…”

“…These changes serve as a trigger of the trigeminovascular system followed by vasoactive neuropeptide release [particularly calcitonin gene-related peptide (CGRP)] and pro-inflammatory reaction. Importantly though, recent data show that different cellular microenvironments and distinct vessel wall anatomical features in meninges and cortex can elicit opposing vascular effects in response to the very same treatment ( 6 ).…”

Duality in response of intracranial vessels to nitroglycerin revealed in rats by imaging photoplethysmography

“…At the same time, the strong constrictive response of dural arterioles did not depend on the type of skull preparation (cranial window or thinned skull) and the type of anesthesia (кetamine/xylazine mixture or urethane). Moreover, both the lack of significant vasodilation in cortical arterioles under urethane anesthesia and weaker dilation of cortical vessels in the case of thinner skull were observed 60 . In other words, in animals under urethane anesthesia and with a closed cranial window (we have similar experimental conditions), only NTG-induced constriction of dural arterioles was de facto observed.…”