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

Abstract

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. Key Words: nitric oxide Ⅲ angiogenesis Ⅲ surfactant Ⅲ respiratory distress syndrome Ⅲ alveolar capillary dysplasia N O is a multifaceted vasodilator that has also been shown to be an important regulator of vascular growth and remodeling. 1 NO has been implicated as a critical downstream mediator in the biological response to a variety of angiogenic growth factors, 2-5 mediating endothelial cell (EC) proliferation, 6 migration, 7 and vascular tube formation. 3 Adult eNOS-deficient mice (eNOS Ϫ/Ϫ ) exhibit marked defects in postnatal angiogenesis, 8 moderate systemic hypertension, 9 and mild elevation in pulmonary vascular resistance with an exaggerated pulmonary vasoconstrictor response to hypoxia. 10 Although eNOS Ϫ/Ϫ mice are viable, litter sizes are characteristically small, and these offspring exhibit minor abnormalities such as bicuspid aortic valve 11 and atrial septal defects. 12 eNOS is strongly expressed in rodent 13 and ovine 14 fetal lungs at mid to late gestation, in both vascular endothelial as well as airway epithelial cells, 15 consistent with a possible role in the regulation of pulmonary vasculature and airway development. However, to date there has been no direct evidence implicating NO in fetal lung development, although recently eNOS has been shown to be involved in compensatory hyperplasia of postnatal lung 16 and in preventing loss of alveolarization during neonatal exposure to hypoxia. 17 The paradox between the important role of NO in postnatal angiogenesis, yet the apparently normal embryonic vascular development in eNOS Ϫ/Ϫ animals could be explained by a high degree of redundancy, which often is as...

Endothelial nitric oxide synthase gene glu298asp polymorphism in preterm neonates with respiratory distress syndrome

“…10 Also, NO modulates immuneregulation, surfactant maturation or secretion. 11 In this study, we found statistical increases in TT, GT+TT genotype and T allele among RDS compared to controls. In the contrary, Poggi et al found that GT+TT is an independent risk factors for bronchopulmonary dysplasia but not RDS.…”

A Role for Macrophage Migration Inhibitory Factor in the Neonatal Respiratory Distress Syndrome

“…First, no age related phenotype of the MIF-KO has previously been reported, although defects in immunologic responsiveness and growth control have been revealed by infectious, immunologic, or oncogenic challenge (19,22,32,35). Secondly, mice genetically deficient in numerous factors have been shown to die at birth due to respiratory distress (26,47,48). By contrast, mouse pups genetically deficient in MIF do not suffer obvious respiratory distress at term birth.…”

The Robyn Barst Memorial Lecture: Differences between the Fetal, Newborn, and Adult Pulmonary Circulations: Relevance for Age‐Specific Therapies (2013 Grover Conference Series)

“…The effects of VEGF during lung development are partly mediated through enhanced NO production, and disruption of endothelial NO synthase (eNOS) expression impairs lung vascular function and growth. 45,46 Lungs of late-fetal and neonatal eNOS-deficient mice have a paucity of distal arteries and reduced alveolarization 45 and are more susceptible to failed vascular and alveolar growth after exposure to mild hypoxia and hyperoxia. 47 Prolonged infusions of SU5416, a VEGF receptor antagonist, cause endothelial dysfunction, with decreased eNOS expression, pulmonary vascular remodeling, and reduced arterial and alveolar growth in late-fetal sheep.…”