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

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    Christian Staehr, 1 Department of Biomedicine, 1006 Aarhus University , Aarhus, Denmark., Lise Hangaard, 1 Department of Biomedicine, 1006 Aarhus University , Aarhus, Denmark., Elena V Bouzinova, 1 Department of Biomedicine, 1006 Aarhus University , Aarhus, Denmark., Sukhan Kim, 1 Department of Biomedicine, 1006 Aarhus University , Aarhus, Denmark.,
  • Rajkumar Rajanathan
  • Peter Boegh Jessen, 1 Department of Biomedicine, 1006 Aarhus University , Aarhus, Denmark., Nathan Luque, 2 Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Queensland, Australia., Zijian Xie, 3 Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, WV, USA.,
  • Karin Lykke-Hartmann
  • Shaun L Sandow, 2 Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Queensland, Australia.,
  • Christian Aalkjaer
  • Vladimir V Matchkov

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.

OriginalsprogEngelsk
TidsskriftJournal of Cerebral Blood Flow and Metabolism
Sider (fra-til)271678X18761712
ISSN0271-678X
DOI
StatusE-pub ahead of print - 1 jan. 2018
Eksternt udgivetJa

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