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

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Abstract
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 ir 2.1 channel expression in cerebrovascular endothelium. Two weeks pNaKtide treatment normalized cerebral artery tone, endothelial K ir 2.1 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.

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