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1 Department of Veterinary Basic Sciences, Royal Veterinary College, London, United Kingdom
2 Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
* To whom correspondence should be addressed. E-mail: Flavahan.1{at}osu.edu.
Cold constricts cutaneous blood vessels by selectively increasing the activity of smooth muscle 
2-adrenoceptors (2-ARs). In mouse tail arteries, 2-AR constriction is mediated by 2A-ARs at 37oC, whereas the cold-induced augmentation in 2-AR activity is mediated entirely by 2C-ARs. Cold causes translocation of 2C-ARs from the transGolgi to the plasma membrane, mediated by cold-induced activation of RhoA and Rho kinase. The present experiments analyzed the mechanisms underlying these responses. Mouse tail arteries were studied in a pressure myograph. Cooling the arteries (28oC) caused a rapid increase in reactive oxygen species (ROS) in smooth muscle cells, determined by confocal microscopy of arteries loaded with the ROS sensitive probes, dichlorodihydrofluorescein or reduced Mitotracker Red. The inhibitor of mitochondrial complex I rotenone (10 µmol/L), the antioxidant N-acetylcysteine (NAC, 20 mmol/L), or the cell-permeable mimic of superoxide dismutase MnTMPyP (50 µmol/L) did not affect vasoconstriction to 2-AR stimulation (UK14304) at 37oC, but dramatically inhibited the response at 28°C. Indeed, these ROS inhibitors abolished the cold-induced increase in 2-AR constrictor activity. NAC (20 mM) or MnTMPyP (50 µmol/L) also abolished the cold-induced activation of RhoA in human cultured vascular smooth muscle cells, and the cold-induced mobilization of 2C-ARs to the cell surface in HEK 293 cells transfected with the receptor. The combined results suggest that cold-induced constriction is mediated by redox signaling in smooth muscle cells, initiated by mitochondrial generation of ROS, which stimulate RhoA/Rho kinase signaling and the subsequent mobilization of 2C-ARs to the cell surface. Altered activity of ROS may contribute to cold-induced vasospasm occurring in Raynaud's phenomenon.
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