Abnormal neurovascular coupling as a cause of excess cerebral vasodilation in familial migraine

Abstract

Aims Acute migraine attack in familial hemiplegic migraine type 2 (FHM2) patients is characterized by sequential hypo- and hyperperfusion. FHM2 is associated with mutations in the Na,K-ATPase α2 isoform. Heterozygous mice bearing one of these mutations (α2+/G301R) were shown to have elevated cerebrovascular tone and, thus, hypoperfusion that might lead to elevated concentrations of local metabolites. We hypothesize that these α2+/G301R mice also have increased cerebrovascular hyperemic responses to these local metabolites leading to hyperperfusion in the affected part of the brain. Methods and Results Neurovascular coupling was compared in α2+/G301R and matching wild type (WT) mice using Laser Speckle Contrast Imaging. In brain slices, parenchymal arteriole diameter and intracellular calcium changes in neuronal tissue, astrocytic endfeet and smooth muscle cells in response to neuronal excitation were assessed. Wall tension and smooth muscle membrane potential were measured in isolated middle cerebral arteries. Quantitative PCR, Western blot and immunohistochemistry were used to assess the molecular background underlying the functional changes. Whisker stimulation induced larger increase in blood perfusion, i.e. hyperemic response, of the somatosensory cortex of α2+/G301R than WT mice. Neuronal excitation was associated with larger parenchymal arteriole dilation in brain slices from α2+/G301R than WT mice. These hyperemic responses in vivo and ex vivo were inhibited by BaCl2, suggesting involvement of inward-rectifying K+ channels (Kir). Relaxation to elevated bath K+ was larger in arteries from α2+/G301R compared to WT mice. This difference was endothelium-dependent. Endothelial Kir2.1 channel expression was higher in arteries from α2+/G301R mice. No sex difference in functional responses and Kir2.1 expression was found. Conclusions This study suggests that an abnormally high cerebrovascular hyperemic response in α2+/G301R mice is a result of increased endothelial Kir2.1 channel expression. This may be initiated by vasospasm-induced accumulation of local metabolites and underlie the hyperperfusion seen in FHM2 patients during migraine attack. Translational Perspective Migraine, especially familial migraine with aura, is strongly associated with severe cerebrovascular events. Acute migraine attack in familial hemiplegic migraine type 2 (FHM2) patients is characterized by transient hypoperfusion, which is followed by hyperperfusion of the affected hemisphere. We have previously described the mechanism responsible for FHM2-associated vasospasm of cerebral arteries and brain hypoperfusion. In this study, we characterize the mechanism for an abnormally strong cerebral vasodilator response that follows vasospasm and causes delayed hyperperfusion in a migraine attack. These defects may contribute to the cerebrovascular damage seen in patients with migraine with aura and are suggestive as future therapeutic targets.

Aether, Fields & Energy Dynamics in Living Bodies - Part III

“…In non-migraineurs individuals neural and vascular activities are tightly coupled with a highly regulated interplay between the two systems to maintain regional blood flow, energy generation, and delivery of metabolic substances [27][28][29]. In migraineurs the state of neurovascular desynchronization fails to return to normal following the migraine attack leading to a chronic state of cortical susceptibility not dissimilar to that seen in seizure disorder.…”

Migraine‐Associated Mutation in the Na,K‐ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function

“…We tested our hypothesis in heterozygous mice carrying the G301R mutation in the Atp1a2 gene 25 (Figure S1 ), which is associated with a severe phenotype in patients with FHM2. 26 The α 2 +/G301R mouse model was previously shown to phenocopy FHM2‐relevant disease traits (ie, neuropsychiatric 25 and cerebrovascular 27 , 28 manifestations). We compared cardiac function in 3‐ and 8‐month‐old α 2 +/G301R mice with age‐matched wild‐type (WT) controls, addressing a progression of the pathology associated with decreased cardiac expression of the Na,K‐ATPase α 2 isoform.…”

Kv1.5 channel mediates monosodium urate-induced activation of NLRP3 inflammasome in macrophages and arrhythmogenic effects of urate on cardiomyocytes

“…3b, 6). The inward-rectifier K + channel inhibitor BaCl 2 [ 20 ] was used to examine the roles of inward-rectifier K + channels. BaCl 2 at 0.1–1 mM did not change the levels of capase-1 and IL-1β (Supplementary Fig.…”