TY - JOUR

T1 - Abnormal neurovascular coupling as a cause of excess cerebral vasodilaion in familial migarine

AU - Staehr, Christian

AU - Rajanathan, Rajkumar

AU - Postnov, Dmitry D.

AU - Hangaard, Lise

AU - Bouzinova, Elena

AU - Lykke-Hartmann, Karin

AU - Bach, Flemming W.

AU - Sandow, Shaun L.

AU - Aalkjaer, Christian

AU - Matchkov, Vladimir V.

PY - 2020

Y1 - 2020

N2 - AIMS Acute migraine attack in familial hemiplegic migraine type 2 (FHM2) patients is characterized by sequential hypoand hyperperfusion. FHM2 is associated with mutations in the Na, K-ATPase cc2 isoform. Heterozygous mice bearing one of these mutations (alpha 2(+/G301R) mice) were shown to have elevated cerebrovascular tone and, thus, hypoperfusion that might lead to elevated concentrations of local metabolites. We hypothesize that these alpha 2(+/G301R) mice also have increased cerebrovascular hyperaemic responses to these Local metabolites Leading to hyperperfusion in the affected part of the brain.Methods and results Neurovascular coupling was compared in alpha 2(+/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 polymerase chain reaction, 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. hyperaemic response, of the somatosensory cortex of alpha 2(+/G301R) than WT mice. Neuronal excitation was associated with larger parenchymal arteriole dilation in brain slices from alpha 2(+/G301R) than WT mice. These hyperaemic responses in vivo and ex vivo were inhibited by BaCl2, suggesting involvement of inward-rectifying K+ channels (K-ir) Relaxation to elevated bath K+ was larger in arteries from oc2 +/G3 degrees 1R compared to WT mice. This difference was endotheliumdependent. Endothelial K-ir-2.1 channel expression was higher in arteries from alpha 2(+/G301R) mice. No sex difference in functional responses and K(ir)2.1 expression was found.Conclusion This study suggests that an abnormally high cerebrovascular hyperaemic response in alpha 2(+/G301R) mice is a result of increased endothelial K(ir)2.1 channel expression. This may be initiated by vasospasm-induced accumulation of local metabolites and underlie the hyperperfusion seen in FHM2 patients during migraine attack.[GRAPHICS].

AB - AIMS Acute migraine attack in familial hemiplegic migraine type 2 (FHM2) patients is characterized by sequential hypoand hyperperfusion. FHM2 is associated with mutations in the Na, K-ATPase cc2 isoform. Heterozygous mice bearing one of these mutations (alpha 2(+/G301R) mice) were shown to have elevated cerebrovascular tone and, thus, hypoperfusion that might lead to elevated concentrations of local metabolites. We hypothesize that these alpha 2(+/G301R) mice also have increased cerebrovascular hyperaemic responses to these Local metabolites Leading to hyperperfusion in the affected part of the brain.Methods and results Neurovascular coupling was compared in alpha 2(+/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 polymerase chain reaction, 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. hyperaemic response, of the somatosensory cortex of alpha 2(+/G301R) than WT mice. Neuronal excitation was associated with larger parenchymal arteriole dilation in brain slices from alpha 2(+/G301R) than WT mice. These hyperaemic responses in vivo and ex vivo were inhibited by BaCl2, suggesting involvement of inward-rectifying K+ channels (K-ir) Relaxation to elevated bath K+ was larger in arteries from oc2 +/G3 degrees 1R compared to WT mice. This difference was endotheliumdependent. Endothelial K-ir-2.1 channel expression was higher in arteries from alpha 2(+/G301R) mice. No sex difference in functional responses and K(ir)2.1 expression was found.Conclusion This study suggests that an abnormally high cerebrovascular hyperaemic response in alpha 2(+/G301R) mice is a result of increased endothelial K(ir)2.1 channel expression. This may be initiated by vasospasm-induced accumulation of local metabolites and underlie the hyperperfusion seen in FHM2 patients during migraine attack.[GRAPHICS].

KW - Endothelium

KW - Inward-rectifying potassium channels

KW - Migraine

KW - Na, K-ATPase

KW - Neurovascular coupling

KW - Cerebral perfusion

KW - PROLONGED MIGRAINE AURA

KW - SPREADING DEPRESSION

KW - CAPILLARY PERICYTES

KW - NEURONAL-ACTIVITY

KW - K+

KW - MECHANISMS

KW - ASTROCYTES

KW - CHANNELS

KW - DYNAMICS

KW - STIMULATION

U2 - 10.1093/cvr/cvz306

DO - 10.1093/cvr/cvz306

M3 - Journal article

C2 - 31710670

VL - 116

SP - 2009

EP - 2020

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 12

ER -