Cooling-induced dilatation of cutaneous arteries is mediated by increased myoendothelial communication

Cold exposure causes cutaneous vasoconstriction via a reflex increase in sympathetic activity and a local effect to augment adrenergic constriction. Local cooling also initiates cutaneous dilatation, which may function to restrain cold-induced constriction. However, the underlying mechanisms and physiological role of cold-induced dilatation have not been defined. Experiments were performed to assess the role of endothelial-derived mediators in this response. In isolated pressurized cutaneous mouse tail arteries, cooling (28°C) did not affect the magnitude of dilatation to acetylcholine in preconstricted arteries. However, inhibition of nitric oxide (NO) [N^G-nitro-l-arginine methyl ester (l-NAME)] and prostacyclin (PGI₂) (indomethacin) reduced acetylcholine-induced dilatation at 37°C but not at 28°C, suggesting that cooling increased NO/PGI₂-independent dilatation. This NO/PGI₂-independent dilatation was reduced by inhibition of endothelial SK (UCL1684) and IK (TRAM34) Ca²⁺-activated K⁺-channels (K_Ca), consistent with endothelium-derived hyperpolarization (EDH). Cooling also increased dilatation to direct activation of K_Ca channels (SKA31, CyPPA) but did not affect dilatation to exogenous NO (DEA-NONOate). This cooling-induced increase in EDH-type dilatations was associated with divergent effects on potential downstream EDH mechanisms: cooling reduced dilatation to K⁺, which mimics an intercellular K⁺ cloud, but increased direct communication between endothelial and smooth muscle cells (myoendothelial coupling), assessed by cellular transfer of biocytin. Indeed, inhibition of gap junctions (carbenoxolone) abolished the EDH-type component of dilatation to acetylcholine during cooling but did affect NO-dominated dilatation at 37°C. Cooling also inhibited U46619 constriction that was prevented by inhibition of IK and SK K_Ca channels or inhibition of gap junctions. The results suggest that cooling dilates cutaneous arteries by increasing myoendothelial communication and amplifying EDH-type dilatation.NEW & NOTEWORTHY Cold causes cutaneous vasoconstriction to restrict heat loss. Although cold also initiates cutaneous dilatation, the mechanisms and role of this dilatation have not been clearly defined. This study demonstrates that cooling increases myoendothelial coupling between smooth muscle and endothelial cells in cutaneous arteries, which is associated with increased endothelium-derived hyperpolarization (EDH)-type dilatation. Dysfunction in this process may contribute to excessive cold-induced constriction and tissue injury.