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 alpha2Cadrenoceptors (alpha2c-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, vibration selectively increased constriction of isolated arteries to sympathetic stimulation and to alpha2-AR activation, which was abolished by alpha2C-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 alpha2c-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 underlying the vibration-induced increase in sympathetic vasoconstriction;
Aim 2 will determine mechanisms underlying the 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.

Agency
National Institute of Health (NIH)
Institute
National Institute for Occupational Safety and Health (NIOSH)
Type
Research Project (R01)
Project #
1R01OH008531-01
Application #
6959114
Study Section
Safety and Occupational Health Study Section (SOH)
Program Officer
Frederick, Linda J
Project Start
2005-08-01
Project End
2006-08-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$229,391
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Zhu, Jian-Hong; Chen, Chun-Lin; Flavahan, Sheila et al. (2011) Cyclic stretch stimulates vascular smooth muscle cell alignment by redox-dependent activation of Notch3. Am J Physiol Heart Circ Physiol 300:H1770-80
Goel, Aditya; Su, Baogen; Flavahan, Sheila et al. (2010) Increased endothelial exocytosis and generation of endothelin-1 contributes to constriction of aged arteries. Circ Res 107:242-51
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Flavahan, Nicholas A (2008) Regulation of vascular reactivity in scleroderma: new insights into Raynaud's phenomenon. Rheum Dis Clin North Am 34:81-7;vii
Eid, A H; Chotani, M A; Mitra, S et al. (2008) Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle alpha2C-adrenoceptors. Am J Physiol Heart Circ Physiol 295:H266-72
Eid, A H; Maiti, K; Mitra, S et al. (2007) Estrogen increases smooth muscle expression of alpha2C-adrenoceptors and cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol 293:H1955-61
Krajnak, K; Dong, R G; Flavahan, S et al. (2006) Acute vibration increases alpha2C-adrenergic smooth muscle constriction and alters thermosensitivity of cutaneous arteries. J Appl Physiol 100:1230-7
Flavahan, Nicholas A (2006) A farewell kiss triggers a broken heart? Circ Res 98:1117-9