Journal article
Targeting Na,K-ATPase-Src signaling to normalize cerebral blood flow in a murine model of familial hemiplegic migraine
Journal of Cerebral Blood Flow and Metabolism, Vol.45(5), pp.842-854
2025
PMID: 39628316
Abstract
Familial hemiplegic migraine type 2 (FHM2) is linked to Na,K-ATPase α2 isoform mutations, including that of G301R. Mice heterozygous for this mutation (α2+/G301R) show cerebrovascular hypercontractility associated with amplified Src kinase signaling, and exaggerated neurovascular coupling. This study hypothesized that targeting Na,K-ATPase-dependent Src phosphorylation with pNaKtide would normalize cerebral perfusion and neurovascular coupling in α2+/G301R mice. The effect of pNaKtide on cerebral blood flow and neurovascular coupling was assessed using laser speckle contrast imaging in awake, head-fixed mice with cranial windows in a longitudinal study design. At baseline, compared to wild type, α2+/G301R mice exhibited increased middle cerebral artery tone; with whisker stimulation leading to an exaggerated increase in sensory cortex blood flow. No difference between genotypes in telemetrically assessed blood pressure occurred. The exaggerated neurovascular coupling in α2+/G301R mice was associated with increased Kir2.1 channel expression in cerebrovascular endothelium. Two weeks pNaKtide treatment normalized cerebral artery tone, endothelial Kir2.1 expression, and neurovascular coupling in α2+/G301R mice. Inhibition of the Na,K-ATPase-dependent Src kinase signaling with pNaKtide prevented excessive vasoconstriction and disturbances in neurovascular coupling in α2+/G301R mice. pNaKtide had only minor hypotensive effect similar in both genotypes. These results demonstrate a novel treatment target to normalize cerebral perfusion in FHM2.Familial hemiplegic migraine type 2 (FHM2) is linked to Na,K-ATPase α2 isoform mutations, including that of G301R. Mice heterozygous for this mutation (α2+/G301R) show cerebrovascular hypercontractility associated with amplified Src kinase signaling, and exaggerated neurovascular coupling. This study hypothesized that targeting Na,K-ATPase-dependent Src phosphorylation with pNaKtide would normalize cerebral perfusion and neurovascular coupling in α2+/G301R mice. The effect of pNaKtide on cerebral blood flow and neurovascular coupling was assessed using laser speckle contrast imaging in awake, head-fixed mice with cranial windows in a longitudinal study design. At baseline, compared to wild type, α2+/G301R mice exhibited increased middle cerebral artery tone; with whisker stimulation leading to an exaggerated increase in sensory cortex blood flow. No difference between genotypes in telemetrically assessed blood pressure occurred. The exaggerated neurovascular coupling in α2+/G301R mice was associated with increased Kir2.1 channel expression in cerebrovascular endothelium. Two weeks pNaKtide treatment normalized cerebral artery tone, endothelial Kir2.1 expression, and neurovascular coupling in α2+/G301R mice. Inhibition of the Na,K-ATPase-dependent Src kinase signaling with pNaKtide prevented excessive vasoconstriction and disturbances in neurovascular coupling in α2+/G301R mice. pNaKtide had only minor hypotensive effect similar in both genotypes. These results demonstrate a novel treatment target to normalize cerebral perfusion in FHM2.
Details
- Title
- Targeting Na,K-ATPase-Src signaling to normalize cerebral blood flow in a murine model of familial hemiplegic migraine
- Authors
- Christian Staehr (Corresponding Author) - Aarhus UniversityHalvor Østerby Guldbrandsen - Aarhus UniversityCasper Homilius - Aarhus UniversityLaura Øllegaard Johnsen - Aarhus UniversityDmitry Postnov - Aarhus UniversityTina M Pedersen - Aarhus UniversitySandrine Pierre - Marshall UniversityShaun L Sandow - University of the Sunshine Coast, Queensland, School of Health - BiomedicineVladimir V Matchkov - Aarhus University
- Publication details
- Journal of Cerebral Blood Flow and Metabolism, Vol.45(5), pp.842-854
- Publisher
- Sage Publications Ltd.
- Date published
- 2025
- DOI
- 10.1177/0271678X241305562
- ISSN
- 1559-7016
- PMID
- 39628316
- Data Availability
- Data is available for this article.
- Grant note
- This study was supported by Riisfort Foundation and Lundbeck Foundation (R344-2020-952, R412-2022-449) and Independent Research Fund Denmark (3101-00103B).
- Organisation Unit
- School of Health - Biomedicine; Healthy Ageing Research Cluster
- Language
- English
- Record Identifier
- 991087297802621
- Output Type
- Journal article
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- Domestic collaboration
- International collaboration
- Web Of Science research areas
- Endocrinology & Metabolism
- Hematology
- Neurosciences
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