eNOS-deficient mice show reduced pulmonary vascular proliferation and remodeling to chronic hypoxia.
Pulmonary hypertension is characterized by structural and morphological changes to the lung vasculature. To determine the potential role of nitric oxide in the vascular remodeling induced by hypoxia, we exposed wild-type [WT(+/+)] and endothelial nitric oxide synthase (eNOS)-deficient [(-/-)] mice to normoxia or hypoxia (10% O(2)) for 2, 4, and 6 days or for 3 wk. Smooth muscle alpha-actin and von Willebrand factor immunohistochemistry revealed significantly less muscularization of small vessels in hypoxic eNOS(-/-) mouse lungs than in WT(+/+) mouse lungs at early time points, a finding that correlated with decreases in proliferating vascular cells (5-bromo-2'-deoxyuridine positive) at 4 and 6 days of hypoxia in the eNOS(-/-) mice. After 3 wk of hypoxia, both mouse types exhibited similar percentages of muscularized small vessels; however, only the WT(+/+) mice exhibited an increase in the percentage of fully muscularized vessels and increased vessel wall thickness. eNOS protein expression was increased in hypoxic WT(+/+) mouse lung homogenates at all time points examined, with significantly increased percentages of small vessels expressing eNOS protein after 3 wk. These results indicate that eNOS deficiency causes decreased muscularization of small pulmonary vessels in hypoxia, likely attributable to the decrease in vascular cell proliferation observed in these mice.
Quinlan
T R
TR
Department of Anesthesiology, University of Virginia, Charlottesville, Virginia 22906, USA.
Li
D
D
Laubach
V E
VE
Shesely
E G
EG
Zhou
N
N
Johns
R A
RA
D000199:Actins / Q000032:analysis; D000818:Animals; D002908:Chronic Disease; D003433:Crosses, Genetic; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D008168:Lung / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000166:cytology* / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011652:Pulmonary Circulation / Q000235:genetics / Q000502:physiology*; D014841:von Willebrand Factor / Q000032:analysis
D000199:Actins; D014841:von Willebrand Factor; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse