Vladimir Matchkov

Smooth muscle Ca2+ sensitization causes hypercontractility of middle cerebral arteries in mice bearing the familial hemiplegic migraine type 2 associated mutation

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Smooth muscle Ca2+ sensitization causes hypercontractility of middle cerebral arteries in mice bearing the familial hemiplegic migraine type 2 associated mutation. / Staehr, Christian; Hangaard, Lise; Bouzinova, Elena V.; Kim, Sukhan; Rajanathan, Rajkumar; Boegh Jessen, Peter; Luque, Nathan; Xie, Zijian; Lykke-Hartmann, Karin; Sandow, Shaun L; Aalkjær, Christian; Matchkov, Vladimir V.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 39, No. 8, 0271678X18761712, 08.2019, p. 1570-1587.

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@article{8340c6e2f32c48f7a3064d74cef61146,
title = "Smooth muscle Ca2+ sensitization causes hypercontractility of middle cerebral arteries in mice bearing the familial hemiplegic migraine type 2 associated mutation",
abstract = "Familial hemiplegic migraine type 2 (FHM2) is associated with inherited point-mutations in the Na,K-ATPase α2 isoform, including G301R mutation. We hypothesized that this mutation affects specific aspects of vascular function, and thus compared cerebral and systemic arteries from heterozygote mice bearing the G301R mutation (Atp1a2+/-G301R) with wild type (WT). Middle cerebral (MCA) and mesenteric small artery (MSA) function was compared in an isometric myograph. Cerebral blood flow was assessed with Laser speckle analysis. Intracellular Ca2+and membrane potential were measured simultaneously. Protein expression was semi-quantified by immunohistochemistry. Protein phosphorylation was analysed by Western blot. MSA from Atp1a2+/-G301Rand WT showed similar contractile responses. The Atp1a2+/-G301RMCA constricted stronger to U46619, endothelin and potassium compared to WT. This was associated with an increased depolarization, although the Ca2+change was smaller than in WT. The enhanced constriction of Atp1a2+/-G301RMCA was associated with increased cSrc activation, stronger sensitization to [Ca2+]iand increased MYPT1 phosphorylation. These differences were abolished by cSrc inhibition. Atp1a2+/-G301Rmice had reduced resting blood flow through MCA in comparison with WT mice . FHM2-associated mutation leads to elevated contractility of MCA due to sensitization of the contractile machinery to Ca2+, which is mediated via Na,K-ATPase/Src-kinase/MYPT1 signalling.",
keywords = "Familial hemiplegic migraine type 2, hypoperfusion, K-ATPase, Na, smooth muscle sensitization to Ca, tyrosine phosphorylation",
author = "Christian Staehr and Lise Hangaard and Bouzinova, {Elena V.} and Sukhan Kim and Rajkumar Rajanathan and {Boegh Jessen}, Peter and Nathan Luque and Zijian Xie and Karin Lykke-Hartmann and Sandow, {Shaun L} and Christian Aalkj{\ae}r and Matchkov, {Vladimir V}",
year = "2019",
month = aug,
doi = "10.1177/0271678X18761712",
language = "English",
volume = "39",
pages = "1570--1587",
journal = "Journal of Cerebral Blood Flow and Metabolism",
issn = "0271-678X",
publisher = "SAGE Publications Ltd",
number = "8",

}

RIS

TY - JOUR

T1 - Smooth muscle Ca2+ sensitization causes hypercontractility of middle cerebral arteries in mice bearing the familial hemiplegic migraine type 2 associated mutation

AU - Staehr, Christian

AU - Hangaard, Lise

AU - Bouzinova, Elena V.

AU - Kim, Sukhan

AU - Rajanathan, Rajkumar

AU - Boegh Jessen, Peter

AU - Luque, Nathan

AU - Xie, Zijian

AU - Lykke-Hartmann, Karin

AU - Sandow, Shaun L

AU - Aalkjær, Christian

AU - Matchkov, Vladimir V

PY - 2019/8

Y1 - 2019/8

N2 - Familial hemiplegic migraine type 2 (FHM2) is associated with inherited point-mutations in the Na,K-ATPase α2 isoform, including G301R mutation. We hypothesized that this mutation affects specific aspects of vascular function, and thus compared cerebral and systemic arteries from heterozygote mice bearing the G301R mutation (Atp1a2+/-G301R) with wild type (WT). Middle cerebral (MCA) and mesenteric small artery (MSA) function was compared in an isometric myograph. Cerebral blood flow was assessed with Laser speckle analysis. Intracellular Ca2+and membrane potential were measured simultaneously. Protein expression was semi-quantified by immunohistochemistry. Protein phosphorylation was analysed by Western blot. MSA from Atp1a2+/-G301Rand WT showed similar contractile responses. The Atp1a2+/-G301RMCA constricted stronger to U46619, endothelin and potassium compared to WT. This was associated with an increased depolarization, although the Ca2+change was smaller than in WT. The enhanced constriction of Atp1a2+/-G301RMCA was associated with increased cSrc activation, stronger sensitization to [Ca2+]iand increased MYPT1 phosphorylation. These differences were abolished by cSrc inhibition. Atp1a2+/-G301Rmice had reduced resting blood flow through MCA in comparison with WT mice . FHM2-associated mutation leads to elevated contractility of MCA due to sensitization of the contractile machinery to Ca2+, which is mediated via Na,K-ATPase/Src-kinase/MYPT1 signalling.

AB - Familial hemiplegic migraine type 2 (FHM2) is associated with inherited point-mutations in the Na,K-ATPase α2 isoform, including G301R mutation. We hypothesized that this mutation affects specific aspects of vascular function, and thus compared cerebral and systemic arteries from heterozygote mice bearing the G301R mutation (Atp1a2+/-G301R) with wild type (WT). Middle cerebral (MCA) and mesenteric small artery (MSA) function was compared in an isometric myograph. Cerebral blood flow was assessed with Laser speckle analysis. Intracellular Ca2+and membrane potential were measured simultaneously. Protein expression was semi-quantified by immunohistochemistry. Protein phosphorylation was analysed by Western blot. MSA from Atp1a2+/-G301Rand WT showed similar contractile responses. The Atp1a2+/-G301RMCA constricted stronger to U46619, endothelin and potassium compared to WT. This was associated with an increased depolarization, although the Ca2+change was smaller than in WT. The enhanced constriction of Atp1a2+/-G301RMCA was associated with increased cSrc activation, stronger sensitization to [Ca2+]iand increased MYPT1 phosphorylation. These differences were abolished by cSrc inhibition. Atp1a2+/-G301Rmice had reduced resting blood flow through MCA in comparison with WT mice . FHM2-associated mutation leads to elevated contractility of MCA due to sensitization of the contractile machinery to Ca2+, which is mediated via Na,K-ATPase/Src-kinase/MYPT1 signalling.

KW - Familial hemiplegic migraine type 2

KW - hypoperfusion

KW - K-ATPase

KW - Na

KW - smooth muscle sensitization to Ca

KW - tyrosine phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=85046029699&partnerID=8YFLogxK

U2 - 10.1177/0271678X18761712

DO - 10.1177/0271678X18761712

M3 - Journal article

C2 - 29513112

VL - 39

SP - 1570

EP - 1587

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 8

M1 - 0271678X18761712

ER -