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1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; and 2 Department of Surgery, University of Virginia Health System, Charlottesville, Virginia 22908
Hypoxia upregulates
endothelial (e) nitric oxide synthase (NOS), but how eNOS affects
soluble guanylate cyclase (sGC) protein expression in hypoxia-induced
pulmonary hypertension is unknown. Wild-type (WT), eNOS-deficient
[eNOS(
/)], and inducible NOS (iNOS)-deficient [iNOS(/)]
mice were used to investigate the effects of lack of NO from different
NOS isoforms on sGC activity and protein expression and its
relationship to the muscularization of the pulmonary vasculature. After
6 days of hypoxic exposure (10% O2), the ratios of the
right ventricle to left ventricle + septum weight (RV/LV+S) and
right ventricle weight to body weight, the lung sGC activity, and
vascular muscularization were determined, and protein analysis for
eNOS, iNOS, and sGC was performed. Results demonstrated that there were
significant increases of RV/LV+S in all animals treated with hypoxia.
In hypoxic WT and iNOS(/) mice, eNOS and sGC 
1- and
1-protein increased twofold; cGMP levels and the number
of muscularized vessels also increased compared with hypoxic
eNOS(/) mice. There was a twofold increase of iNOS protein in WT
and eNOS(/) mice, and the basal iNOS protein concentration was
higher in eNOS(/) mice than in WT mice. In contrast, the eNOS(/) mouse lung showed no eNOS protein expression, lower cGMP
concentrations, and no change of sGC protein levels after hypoxic
exposure compared with its normoxic controls (P > 0.34). These results suggest that eNOS, but not iNOS, is a major
regulator of sGC activity and protein expression in the pulmonary vasculature.
nitric oxide; vascular remodeling; pulmonary hypertension; endothelial nitric oxide synthase
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