Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
Am J Physiol Heart Circ Physiol. 2020 Jul 1;319(1):H123-H132. doi: 10.1152/ajpheart.00159.2020. Epub 2020 May 29.
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) [-nitro-l-arginine methyl ester (l-NAME)] and prostacyclin (PGI) (indomethacin) reduced acetylcholine-induced dilatation at 37°C but not at 28°C, suggesting that cooling increased NO/PGI-independent dilatation. This NO/PGI-independent dilatation was reduced by inhibition of endothelial SK (UCL1684) and IK (TRAM34) Ca-activated K-channels (K), consistent with endothelium-derived hyperpolarization (EDH). Cooling also increased dilatation to direct activation of K 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 channels or inhibition of gap junctions. The results suggest that cooling dilates cutaneous arteries by increasing myoendothelial communication and amplifying EDH-type dilatation. 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.
冷暴露通过反射性增加交感神经活动和局部效应增强肾上腺素能收缩引起皮肤血管收缩。局部冷却也会引发皮肤扩张，这可能有助于抑制冷诱导的收缩。然而，冷诱导扩张的潜在机制和生理作用尚未确定。进行了实验以评估内皮衍生介质在这种反应中的作用。在分离的加压鼠尾皮动脉中，冷却（28°C）不会影响预先收缩的动脉对乙酰胆碱扩张的幅度。然而，一氧化氮（NO）抑制[-硝基-L-精氨酸甲酯（L-NAME）]和前列环素（PGI）（吲哚美辛）降低了 37°C 时但不是 28°C 时乙酰胆碱诱导的扩张，表明冷却增加了非一氧化氮/前列环素依赖性扩张。这种非一氧化氮/前列环素依赖性扩张被内皮 SK（UCL1684）和 IK（TRAM34）钙激活 K 通道（K）的抑制所减少，这与内皮衍生的超极化（EDH）一致。冷却还增加了对直接激活 K 通道（SKA31、CyPPA）的扩张，但对外源性 NO（DEA-NONOate）的扩张没有影响。这种冷诱导的 EDH 型扩张与对潜在下游 EDH 机制的不同影响相关：冷降低了对 K 的扩张，这模拟了细胞间的 K 云，但增加了内皮细胞和平滑肌细胞之间的直接通讯（myoendothelial coupling），通过生物胞素的细胞转移来评估。事实上，间隙连接抑制（carbenoxolone）消除了冷时乙酰胆碱扩张的 EDH 型成分，但不影响 37°C 时占主导地位的一氧化氮扩张。冷却还抑制了 U46619 收缩，这种收缩可以通过抑制 IK 和 SK K 通道或抑制间隙连接来预防。结果表明，冷却通过增加肌内皮通讯和放大 EDH 型扩张来扩张皮肤动脉。冷导致皮肤血管收缩以限制热量损失。尽管冷也会引发皮肤扩张，但这种扩张的机制和作用尚未明确界定。本研究表明，冷却增加了皮肤动脉中平滑肌和内皮细胞之间的肌内皮偶联，这与内皮衍生的超极化（EDH）型扩张增加有关。这个过程的功能障碍可能导致过度的冷诱导收缩和组织损伤。
