Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3.
Chronic hypoxia induces pulmonary hypertension and right ventricular (RV) hypertrophy. Nitric oxide (NO) has been proposed to modulate the pulmonary vascular response to hypoxia. We investigated the effects of congenital deficiency of endothelial NO synthase (NOS3) on the pulmonary vascular responses to breathing 11% oxygen for 3-6 wk. After 3 wk of hypoxia, RV systolic pressure was greater in NOS3-deficient than in wild-type mice (35+/-2 vs 28+/-1 mmHg, x+/-SE, P < 0.001). Pulmonary artery pressure (PPA) and incremental total pulmonary vascular resistance (RPI) were greater in NOS3-deficient than in wild-type mice (PPA 22+/-1 vs 19+/-1 mmHg, P < 0.05 and RPI 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, the increase of RV free wall thickness, measured by transesophageal echocardiography, and of RV weight/body weight ratio were more marked in NOS3-deficient mice than in wild-type mice (RV wall thickness 0.67+/-0.05 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 chronic hypoxia was prevented by breathing 20 parts per million NO in both genotypes of mice. These results suggest that congenital NOS3 deficiency enhances hypoxic pulmonary vascular remodeling and hypertension, and RV hypertrophy, and that NO production by NOS3 is vital to counterbalance pulmonary vasoconstriction caused by chronic hypoxic stress.
Steudel
W
W
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Scherrer-Crosbie
M
M
Bloch
K D
KD
Weimann
J
J
Huang
P L
PL
Jones
R C
RC
Picard
M H
MH
Zapol
W M
WM
D000818:Animals; D001835:Body Weight; D002908:Chronic Disease; D004452:Echocardiography; D005260:Female; D006400:Hematocrit; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000209:etiology*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology*; D000860:Hypoxia / Q000150:complications*; D008168:Lung / Q000098:blood supply; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000172:deficiency*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009929:Organ Size; D011086:Polycythemia / Q000150:complications
D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse