Mechanisms of Vascular Dysfunction in Vibration Injury

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Hand-arm vibration syndrome (HAVS) causes considerable morbidity among workers exposed to vibration. The vascular component of HAVS is associated with increased vasoconstriction of finger digital arteries in response to cold exposure. The mechanisms contributing to this vascular disorder are unknown, which makes it difficult to monitor susceptibility or progression of the disease. A major goal of this proposal is to provide molecular insight this vascular dysfunction, so as to generate mechanism-based criteria that will improve diagnosis, monitoring and prevention of the disease. We demonstrate that cold-induced constriction of cutaneous arteries is caused by cold-induced generation of reactive oxygen species (ROS) from smooth muscle cell mitochondria that activate RhoA and Rho kinase, with the subsequent translocation of CC2C- adrenoceptors (cc2c-ARs) from the Golgi to the cell surface. Once there, these receptors respond to activation by norepinephrine and initiate cold-induced constriction. This pathway is targeted by vibration in cutaneous arteries. In a rat tail model that mimics the biodynamic response of human fingers, vibrationselectively increased constriction of isolated arteries to sympathetic stimulation and to aa-AR activation, which was abolished by OC2C-AR inhibition. Vibration also increased cold-induced constriction mediated by these receptors. The effects of vibration were associated with increased activity of Rho kinase, and with a ROS- dependent dysfunction of endothelial relaxation to acetylchpline. We propose that vibration initiates vascular disease by causing oxidant stress in cutaneous arteries resulting in endothelial cell dysfunction, activation of VSM Rho kinase and inappropriate mobilization of oi2c-ARs, increased sympathetic constriction and increased sensitivity to cold-induced constriction. Three Specific Aims are proposed to analyze the effects of acute and chronic exposure of cutaneous arteries to differing intensities of vibration exposure: Aim 1 will determine mechanisms underlyingthe vibration-induced increase in sympathetic vasoconstriction; Aim 2 will determine mechanisms underlyingthe vibration-induced increase in cold sensitivity of cutaneous arteries; and Aim 3 will determine the effects of vibration on endothelial cell function and vascular structure