Targeting Na,K-ATPase-Src signaling to normalize cerebral blood flow in a murine model of familial hemiplegic migraine

TY - JOUR

T1 - Targeting Na,K-ATPase-Src signaling to normalize cerebral blood flow in a murine model of familial hemiplegic migraine

AU - Staehr, Christian

AU - Guldbrandsen, Halvor Østerby

AU - Homilius, Casper

AU - Johnsen, Laura Øllegaard

AU - Postnov, Dmitry

AU - Pedersen, Tina M

AU - Pierre, Sandrine

AU - Sandow, Shaun L

AU - Matchkov, Vladimir V

PY - 2024/12/4

Y1 - 2024/12/4

N2 - Familial hemiplegic migraine type 2 (FHM2) is linked to Na,K-ATPase α 2 isoform mutations, including that of G301R. Mice heterozygous for this mutation ( α 2 + / G3 0 1R ) 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 α 2 + / G3 0 1R 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, α 2 + / G3 0 1R 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 α 2 + / G3 0 1R mice was associated with increased K ir2.1 channel expression in cerebrovascular endothelium. Two weeks pNaKtide treatment normalized cerebral artery tone, endothelial K ir2.1 expression, and neurovascular coupling in α 2 + / G3 0 1R mice. Inhibition of the Na,K-ATPase-dependent Src kinase signaling with pNaKtide prevented excessive vasoconstriction and disturbances in neurovascular coupling in α 2 + / G3 0 1R mice. pNaKtide had only minor hypotensive effect similar in both genotypes. These results demonstrate a novel treatment target to normalize cerebral perfusion in FHM2.

AB - Familial hemiplegic migraine type 2 (FHM2) is linked to Na,K-ATPase α 2 isoform mutations, including that of G301R. Mice heterozygous for this mutation ( α 2 + / G3 0 1R ) 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 α 2 + / G3 0 1R 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, α 2 + / G3 0 1R 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 α 2 + / G3 0 1R mice was associated with increased K ir2.1 channel expression in cerebrovascular endothelium. Two weeks pNaKtide treatment normalized cerebral artery tone, endothelial K ir2.1 expression, and neurovascular coupling in α 2 + / G3 0 1R mice. Inhibition of the Na,K-ATPase-dependent Src kinase signaling with pNaKtide prevented excessive vasoconstriction and disturbances in neurovascular coupling in α 2 + / G3 0 1R mice. pNaKtide had only minor hypotensive effect similar in both genotypes. These results demonstrate a novel treatment target to normalize cerebral perfusion in FHM2.

U2 - 10.1177/0271678X241305562

DO - 10.1177/0271678X241305562

M3 - Journal article

C2 - 39628316

SN - 0271-678X

SP - 271678X241305562

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

ER -