Chronic hypoxia increases endothelial nitric oxide synthase expression in rat lung despite reduced blood flow due to left pulmonary artery stenosis

Regulation of endothelial nitric oxide synthase (eNOS) expression is influenced by multiple factors, including hemodynamics and oxygen tension. Lung eNOS expression is upregulated with chronic hypoxia-induced pulmonary hypertension in rats. To determine whether the increase in eNOS with chronic hypoxia is due to changes in hemodynamics or hypoxia itself, we studied rats 3 weeks after left pulmonary artery stenosis (LPAS). LPAS in normoxic rats reduced the proportion of blood flow to the left lung from 53±1% to 6±2%, and increased the proportion of flow to the right lung from 47±2% to 94±2%. In normoxic LPAS rats eNOS content in the left lung was decreased by 32±7% (p<0.05) compared to sham controls, but there was no increase in eNOS in the right lung with increased flow. LPAS in hypoxic rats reduced the proportion of blood flow to the left lung from 50±1% to 12±3%, and increased the proportion of flow to the right lung from 50±2% to 88±3%. After 3 weeks of hypoxia, LPAS rats showed increased lung eNOS protein expression (1.7 fold), but no significant difference between left and right lung eNOS content, despite reduced flow and pressure to the left lung and increased flow and pressure to the right lung.These findings suggest that chronic hypoxia increases eNOS expression independent of changes in blood flow and pressure, and that hypoxia is the primary stimulus for the increase in lung eNOS expression seen in hypoxic pulmonary hypertension in rats.