SUSTAINED PULMONARY-HYPERTENSION AND RIGHT-VENTRICULAR HYPERTROPHY AFTER CHRONIC HYPOXIA IN MICE WITH CONGENITAL DEFICIENCY OF NITRIC-OXIDESYNTHASE-3

Chronic hypoxia induces pulmonary hypertension and right ventricular ( RV) hypertrophy. Nitric oxide (NO) has been proposed to modulate the p ulmonary vascular response to hypoxia. We investigated the effects of congenital deficiency of endothelial NO synthase (NOS3) on the pulmona ry vascular responses to breathing 11% oxygen for 36 wk, After 3 wk of hypoxia, RV systolic pressure was greater in NOS3-deficient than in w ild-type mice (35+/-2 vs 28+/-1 mmHg, (x) over bar+/-SE < 0.001), Pulm onary artery pressure (P-PA) and incremental total pulmonary vascular resistance (R-PI) were greater in NOS3-deficient than in wild-type mic e (PPA 22+/-1 vs 19+/-1 mmHg, P < 0.05 and R-PI 92+/-11 vs 55+/-5 mmHg .min.gram.ml(-1), P < 0.05), Morphometry revealed that the proportion of muscularized small pulmonary vessels was almost fourfold greater in NOS3-deficient mice than in wild-type mice. After 6 wk of hypoxia, th e increase of RV free wall thickness, measured by transesophageal echo cardiography, and of RV weight/body weight ratio mere more marked in N OS3-deficient mice than in wildtype mice (RV wall thickness 0.67+/-0.0 5 vs 0.48+/-0.02 mm, P < 0.01 and RV weight/body weight ratio 2.1+/-0. 2 vs 1.6+/-0.1 mg.gram(-1), P < 0.05), RV hypertrophy produced by chro nic hypoxia was prevented by breathing 20 parts per million NO in both genotypes of mice. These results suggest that congenital NOS3 deficie ncy enhances hypoxic pulmonary vascular remodeling and hypertension, a nd RV hypertrophy, and that NO production by NOS3 is vital to counterb alance pulmonary vasoconstriction caused by chronic hypoxic stress.