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(Circulation Research. 2004;94:1115.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Defective Lung Vascular Development and Fatal Respiratory Distress in Endothelial NO Synthase-Deficient Mice

A Model of Alveolar Capillary Dysplasia?

Robin N.N. Han, Saeid Babaei, Malcolm Robb, Tony Lee, Ross Ridsdale, Cameron Ackerley, Martin Post, Duncan J. Stewart

From Terrence Donnelly Heart Center (R.N.N.H., S.B., M.B., T.L., D.J.S.), Division of Cardiology, St Michael’s Hospital and the Department of Medicine, University of Toronto; Hospital for Sick Children (R.R., C.A., M.P.), Toronto, Canada.

Correspondence to Dr Duncan J. Stewart, Director, Division of Cardiology and Dexter Man Chair, University of Toronto, Head of Cardiology, St Michael’s Hospital, 30 Bond St, Suite 7081 Queen Wing, Toronto, Canada. E-mail Stewartd{at}smh.toronto.on.ca

Endothelium-derived NO plays a critical role in the regulation of cardiovascular function and structure, as well as acting as a downstream mediator of the angiogenic response to numerous vascular growth factors. Although endothelial NO synthase (eNOS)-deficient mice are viable, minor congenital cardiac abnormalities have been reported and homozygous offspring exhibit high neonatal mortality out of proportion to the severity of these defects. The aim of the present report was to determine whether abnormalities of the pulmonary vascular development could contribute to high neonatal loss in eNOS-deficient animals. We now report that eNOS-deficient mice display major defects in lung morphogenesis, resulting in respiratory distress and death within the first hours of life in the majority of animals. Histological and molecular examination of preterm and newborn mutant lungs demonstrated marked thickening of saccular septae, with evidence of reduced surfactant material. Lungs of eNOS-deficient mice also exhibited a striking paucity of distal arteriolar branches and extensive regions of capillary hypoperfusion, together with misalignment of pulmonary veins, which represent the characteristic features of alveolar capillary dysplasia. We conclude that eNOS plays a previously unrecognized role in lung development, which may have relevance for clinical syndromes of neonatal respiratory distress.

Key Words: nitric oxide • angiogenesis • surfactant • respiratory distress syndrome • alveolar capillary dysplasia

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