Fetal, but Not Postnatal, Deletion of Semaphorin-Neuropilin-1 Signaling Affects Murine Alveolar Development

The disruption of angiogenic pathways, whether through genetic predisposition or as a consequence of life-saving interventions, may underlie many pulmonary diseases of infancy, including bronchopulmonary dysplasia. Neuropilin-1 (Nrp1) is a transmembrane receptor that plays essential roles in normal and pathological vascular development and binds two distinct ligand families: vascular endothelial growth factor (Vegf) and class 3 semaphorins (Sema3). Although Nrp1 is critical for systemic vascular development, the importance of Nrp1 in pulmonary vascular morphogenesis is uncertain. We hypothesized that Sema3-Nrp1 and Vegf-Nrp1 interactions are important pathways in the orchestration of pulmonary vascular development during alveolarization. Complete ablation of Nrp1 signaling would therefore lead to interruption of normal angiogenic and vascular maturation processes that are relevant to the pathogenesis of bronchopulmonary dysplasia. We have previously shown that congenital loss of Sema3-Nrp1 signaling in transgenic Nrp1(Sema) mice resulted in disrupted alveolar-capillary interface formation and high neonatalmortality. Here, pathohistological examination of Nrp1(Sema-) survivors in the alveolar period revealed moderate to severe respiratory distress, alveolar hemorrhaging, abnormally dilated capillaries, and disintegrating alveolar septa, demonstrating continue dinstability of the alveolar-capillary interface. Moreover, consistent with a reduced capillary density and consequent increases in vascular resistance, hypertensive remodeling was observed. In contrast, conditional Nrp1 deletion beginning at postnatal day 5 had only a transient effect upon alveolar and vascular development or pneumocyte differentiation despiteanincreasein mortality. Our results demonstrate that although Sema3-Nrp1 signaling is critical during fetal pulmonary development, Nrp1 signaling does not appear to be essential for alveolar development or vascular function in the postnatal period.