Vladimir Matchkov
Professor, Department of Biomedicine, Aarhus University
“Ups and downs of the Na,K-ATPase role in cerebral perfusion”
Abstract (Matchkov): Na,K-ATPase is essential for maintaining cellular ion homeostasis, but it also activates intracellular signaling pathways independent of ion transport. We identified a role for Na,K-ATPase–dependent Src kinase signaling in sensitizing smooth muscle contractility to intracellular Ca²⁺, thereby influencing cerebrovascular tone. This pathway is implicated in Familial Hemiplegic Migraine type 2 (FHM2), which involves mutations in the Na,K-ATPase α2 isoform. Mice carrying FHM2 mutations show elevated cerebrovascular tone and reduced brain perfusion, partially compensated by enhanced endothelial Kir2.1 channel function. This adaptation increases neurovascular responses, contributing to perfusion abnormalities in FHM2 and offering therapeutic potential. Indeed, chronic inhibition of Na,K-ATPase–Src signaling restores cerebrovascular tone and neurovascular coupling in FHM2 model.Ischemia disrupts K⁺ homeostasis in the neurovascular unit and suppresses Na,K-ATPase activity, leading to Src-dependent microvascular constriction, particularly via pericytes, and exacerbating stroke outcomes. However, targeting Src signaling alone does not improve recovery, indicating that additional mechanisms, such as Ca²⁺-activated Cl⁻ channels, may contribute.
Rune Enger
Professor, Institute of Basic Medical Sciences, University of Oslo
“AQP4 dynamics in astrocyte endfeet”
Abstract (Enger): Perivascular astrocytic endfeet, highly enriched with the water channel aquaporin 4 (AQP4), are central to efficient perivascular fluid flow and solute clearance from the brain. However, how AQP4 promotes solute movement at the brain borders is unclear. We have shown that the astrocyte endfoot sleeve is a dynamic structure that dilates and constricts with vascular dynamics. We hypothesized that AQP4 could modulate this mechanical coupling. Using biophysical modeling with realistic brain tissue geometries, we find that increased water permeability in endfeet is unlikely to account for the effects of AQP4 on extracellular solute movement. Our experimental data rather suggest that AQP4 enables endfeet to act as a relatively rigid outer wall of the perivascular space, thereby facilitating efficient perivascular fluid dynamics.