Endothelial Arf6 sustains electrical signaling and cerebral blood flow in mice through PIP₂-dependent activation of Kir2.1 channels.

Authors

Maria F Noterman-Soulinthavong, María Sancho, Saúl Huerta de la Cruz, Michael Yarboro, Maurizio Mandalà, Masayo Koide, Nathalie Beaufort, Katalin Todorov-Völgyi, Emma Moreland, David Hill-Eubanks, Martin Dichgans, Mark T Nelson

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 28. Pages e2615120123. Jul 14, 2026. Epub Jul 07, 2026.

Abstract

Brain capillaries sense neural activity and direct blood flow to active regions-a process termed neurovascular coupling that underlies activity-dependent increases in local perfusion (functional hyperemia). A key contributor to functional hyperemic responses is the capillary endothelial cell (cEC) inward rectifier K⁺ (Kir2.1) channel, which, when activated by neuronal activity-derived extracellular K⁺, initiates vasodilatory electrical signals that propagate through the vascular network. Kir2.1 channel function requires continual production of its lipid cofactor, phosphatidylinositol-4,5-bisphosphate (PIP₂), and is compromised in mouse models of cerebral small vessel (cSVD). Although decreased PIP₂ availability is a common feature of cSVDs, mechanisms underlying PIP₂ synthesis remain poorly understood. We hypothesized that Arf6, a small GTPase expressed in cECs that stimulates PIP₂ production, is critical for this process. Using patch-clamp electrophysiology, we demonstrate that inhibiting Arf6 activity progressively decreased cEC Kir2.1 channel activity. This deficit manifested as loss of capillary-to-arteriole electrical signaling in isolated vessels and diminished functional hyperemia in vivo. Exogenously provided PIP₂ restored Kir2.1 currents and functional hyperemia after Arf6 inhibition or genetic knockdown. Collectively, our data suggest that cEC Arf6 sustains Kir2.1 activity by maintaining PIP₂ levels and demonstrate that diminished PIP₂ synthesis is sufficient to impair functional hyperemia. Furthermore, we identify Arf6 as a mechanistic link between PIP₂ production and endothelial electrical signaling, highlighting Arf6 as a potential therapeutic target for restoring functional hyperemia.

PMID:
42412927
Bibliographic data and abstract were imported from PubMed on 08 Jul 2026.

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