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.
Highlights
Vascular headaches were traditionally associated with abnormal changes in blood flow in the intracranial vessels [1], and nowadays the role of vessels in primary or secondary headaches remains a matter of continuous debate [2,3,4,5,6,7]
We explored the effects of GTN on the cerebral circulation with unprecedented temporal and spatial resolution by using two-photon laser scanning microscopy (TPLSM) in anesthetized rats, where vessels were visualized by an i.v. injection of FITC dextran
Visualization of meningeal and cortical vessels and distinguishing arteries from veins Acquisition of z-stacks in a time-lapse mode followed by the reconstruction of 3D images (Figure 1) allowed us to clearly distinguish meningeal blood vessels from the cortical vessels
Summary
Vascular headaches were traditionally associated with abnormal changes in blood flow in the intracranial vessels [1], and nowadays the role of vessels in primary or secondary headaches remains a matter of continuous debate [2,3,4,5,6,7]. In animal models, closed cranial window with intravital epifluorescence microscopy is one of the best established methods since the end of 90s [9]. Both in human and animal studies, observational methods are often complemented with a triggering method, commonly the administration of the NO donor glyceryltrinitrate (GTN) [10,11,12,13]. This medicine is known for its ability to trigger headaches in healthy subjects and to initiate migraine attacks in patients [11,14,15]. There are two phases of the GTN-induced headache: the initial pain starts immediately after GNT infusion and persists only for about
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