Abnormal neurovascular coupling as a cause of excess cerebral vasodilaion in familial migarine
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Abnormal neurovascular coupling as a cause of excess cerebral vasodilaion in familial migarine. / Staehr, Christian; Rajanathan, Rajkumar; Postnov, Dmitry D.; Hangaard, Lise; Bouzinova, Elena; Lykke-Hartmann, Karin; Bach, Flemming W.; Sandow, Shaun L.; Aalkjaer, Christian; Matchkov, Vladimir V.
I: Cardiovascular Research, Bind 116, Nr. 12, 2020, s. 2009-2020.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 256934941