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Departments of 1 Medicine and 3 Pharmacology, Duke University Medical Center, Durham 27710; and 2 Division of Human Studies, Environmental Protection Agency, Chapel Hill, North Carolina 27514
CO is a biologically active gas
that produces cellular effects by multiple mechanisms. Because cellular
binding of CO by heme proteins is increased in hypoxia, we tested the
hypothesis that CO interferes with hypoxic pulmonary vascular
remodeling in vivo. Rats were exposed to inspired CO (50 parts/million)
at sea level or 18,000 ft of altitude [hypobaric hypoxia (HH)], and
changes in vessel morphometry and pulmonary pressure-flow relationships were compared with controls. Vascular cell single strand DNA
(ssDNA) and proliferating cell nuclear antigen (PCNA) were assessed,
and changes in gene and protein expression of smooth muscle 
-actin (sm--actin), 
-actin, and heme oxygenase-1 (HO-1) were evaluated by Western analysis, RT-PCR, and immunohistochemistry. After 21 days of
HH, vascular pressure at constant flow and vessel wall thickness
increased and lumen diameter of small arteries decreased significantly.
The presence of CO, however, further increased both pulmonary vascular
resistance (PVR) and the number of small muscular vessels compared with
HH alone. CO + HH also increased vascular PCNA and nuclear
ssDNA expression compared with hypoxia, suggesting accelerated cell
turnover. CO in hypoxia downregulated sm--actin and strongly
upregulated -actin. CO also increased lung HO activity and HO-1 mRNA
and protein expression in small pulmonary arteries during hypoxia.
These data indicate an overall propensity of CO in HH to promote
vascular remodeling and increase PVR in vivo.
pulmonary hypertension; hypoxic pulmonary vasoconstriction; actin; heme oxygenase
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