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

Author:

Staehr Christian1,Hangaard Lise1,Bouzinova Elena V1,Kim Sukhan1,Rajanathan Rajkumar1,Boegh Jessen Peter1,Luque Nathan2,Xie Zijian3,Lykke-Hartmann Karin1,Sandow Shaun L2,Aalkjaer Christian1,Matchkov Vladimir V1ORCID

Affiliation:

1. Department of Biomedicine, Aarhus University, Aarhus, Denmark

2. Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Queensland, Australia

3. Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, WV, USA

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+/−G301R and WT showed similar contractile responses. The Atp1a2+/−G301R MCA 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+/−G301R MCA was associated with increased cSrc activation, stronger sensitization to [Ca2+]i and increased MYPT1 phosphorylation. These differences were abolished by cSrc inhibition. Atp1a2+/−G301R mice 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.

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Neurology (clinical),Neurology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3