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1 Department of Pathology, University of British Columbia, Vancouver, BC, Canada
* To whom correspondence should be addressed. E-mail: jlwright{at}interchange.ubc.ca.
The pathogenesis of pulmonary hypertension in patients with COPD is not understood. We have previously shown increased levels of mediators that control vasoconstriction (endothelin-1), vascular cell proliferation (endothelin-1 and vascular endothelial growth factor), and vasodilation (endothelial nitric oxide synthase) in the intrapulmonary arteries of animals exposed to cigarette smoke. To determine whether these mediators could be implicated in the structural remodeling of the arterial vasculature and increased pulmonary arterial pressure caused by chronic cigarette smoke exposure, guinea pigs were exposed to daily cigarette smoke for six months. Pulmonary artery pressures were measured. Intrapulmonary artery structure was analyzed by morphometry, artery mediator protein expression by immunohistochemistry, and artery mediator gene expression by laser capture microdissection and real time reverse transcription polymerase chain reaction. We found that the smoke exposed animals developed increases in pulmonary artery pressure and increased muscularization of the small pulmonary arteries. Gene expression and protein levels of all three mediators were increased, and pulmonary artery pressure correlated with both the levels of mediator production and with the degree of arterial muscularization. We conclude that chronic smoke exposure produces increased vasoactive mediator expression in the small intrapulmonary arteries, and these mediators are associated with vascular remodeling as well as increased pulmonary arterial pressure. These findings support the idea that hypertension in COPD is a result of direct cigarette smoke-mediated effects on the vasculature, and suggest that interference with endothelin and VEGF production/activity, or augmentation of nitric oxide levels, may be beneficial.
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