Defective Lung Vascular Development and Fatal Respiratory Distress in Endothelial NO Synthase–Deficient Mice: A Model of Alveolar Capillary Dysplasia?

• Published in: Circulation research Vol. 94; no. 8; pp. 1115 - 1123
• Main Authors: Han, Robin N.N, Babaei, Saeid, Robb, Malcolm, Lee, Tony, Ridsdale, Ross, Ackerley, Cameron, Post, Martin, Stewart, Duncan J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 30-04-2004; Lippincott
• Subjects: Animals; Animals, Newborn; Apoptosis - drug effects; Basement Membrane - ultrastructure; Biological and medical sciences; Capillaries - pathology; Enzyme Induction; Enzyme Inhibitors - pharmacology; Extracellular Matrix - ultrastructure; Female; Fetal Proteins - deficiency; Fetal Proteins - physiology; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Developmental; Growth Substances - biosynthesis; Growth Substances - genetics; Heart Defects, Congenital - embryology; Heart Defects, Congenital - genetics; Humans; Infant, Newborn; Litter Size - drug effects; Litter Size - genetics; Lung - embryology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Neovascularization, Physiologic - genetics; NG-Nitroarginine Methyl Ester - pharmacology; NG-Nitroarginine Methyl Ester - toxicity; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - physiology; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Obstetric Labor, Premature; Pneumology; Pregnancy; Pulmonary Alveoli - blood supply; Pulmonary Surfactants - metabolism; Receptors, Growth Factor - biosynthesis; Receptors, Growth Factor - genetics; Respiratory Distress Syndrome, Newborn - embryology; Respiratory Distress Syndrome, Newborn - enzymology; Respiratory Distress Syndrome, Newborn - genetics; Respiratory system : syndromes and miscellaneous diseases; Vertebrates: cardiovascular system; Animal model; Dysplasia; Respiratory disease; Enzyme; Lung; Rodentia; Synthase; Respiratory system; respiratory distress syndrome; Angiogenesis; alveolar capillary dysplasia; Vertebrata; Mammalia; Mouse; Nitric oxide; Development; Respiratory distress; Circulatory system; surfactant
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000125624.85852.1E

ABSTRACT—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.