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Long distance conduction of vasodilation in the microcirculation: Impact of oxidative stress on electromechanical coupling
Abstract   Peer reviewed

Long distance conduction of vasodilation in the microcirculation: Impact of oxidative stress on electromechanical coupling

C E Hill, S E Wolfe, D J Chaston, L Howitt, Shaun L Sandow and F R Edwards
Journal of Vascular Research, Vol.49(Supplement 1), p.16
Australian and New Zealand Microcirculation Society Meeting, 15th (Margaret River, Australia, 30-Nov-2011–03-Dec-2011)
2012
DOI: https://doi.org/10.1159/000334223
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https://doi.org/10.1159/000334223View
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Abstract

Medical and Health Sciences vasodilation microcirculation electromechanical coupling hyperpolarisation
Increases in tissue blood flow in response to metabolic demand result from the rapid propagation of vasodilation from microcirculatory arterioles to feed arteries. This occurs due to the spread of hyperpolarisation through gap junctions inducing synchronous closure of voltage dependent calcium channels (VDCCs) to coordinate vasodilation over distance. While the hyperpolarisation should decay electrotonically with distance, the dilation spreads upstream without attenuation. We investigated whether this resulted from a nonlinear relationship between hyperpolarisation and relaxation. Microcirculatory arterioles of the cremaster muscle in vivo were studied with anatomical, electrophysiological and computational modelling techniques. Focal application of acetylcholine evoked hyperpolarisation which decayed with distance from the application site, while the spread of vasodilation was unimpaired. The relationship between membrane potential and vascular tone was fitted with 2-line linear regression and threshold potential of -35mV, beyond which dilation was maximal. Reduction in the initial hyperpolarisation amplitude resulted in a decaying hyperpolarisation and dilation, as the threshold was reached closer to the stimulation site. Using a computational model of the vessel wall, the unattenuated dilation could be mimicked by applying the experimentally-determined threshold potential. Experiments using the Connexin40 knockout mouse (Cx40KO), a model of endothelial dysfunction in which endothelial gap junctional coupling is reduced, revealed that the threshold potential was changed from -35mV to -45 mV. Pharmacological experiments indicated an increased contribution of T-type versus L-type VDCCs to arteriolar vascular tone in Cx40KO compared to WT mice and increased expression of T-type channels in vascular smooth muscle cells. The increased contribution of T-type channels to vascular tone was abolished by inhibition of reactive oxygen species (ROS; 1 mM tempol) in arterioles of Cx40KO, but not wildtype mice. We conclude that the mechanism underlying the unimpaired spread of dilation depends on a nonlinear relationship between membrane potential and vasodilation such that dilation remains unattenuated if the hyperpolarisation is greater than the threshold, but decays linearly with hyperpolarisation once the threshold potential is reached. During cardiovascular disease, increased ROS promote increased T-type channel expression and activity and a change in electromechanical coupling underlying the control of vascular tone. This alteration in electromechanical coupling can impact negatively on the ability of arterial networks to respond efficiently to increased metabolic demand.

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