1 Physiology and Experimental Medicine Program, Hospital for Sick Children, Toronto, Ontario, Canada; and.
Am J Respir Cell Mol Biol. 2013 Oct;49(4):627-36. doi: 10.1165/rcmb.2012-0407OC.
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 neonatal mortality. 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 continued instability 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 despite an increase in 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.
血管生成途径的破坏，无论是通过遗传易感性还是作为救生干预的结果，可能是许多婴儿期肺部疾病的基础，包括支气管肺发育不良。神经纤毛蛋白-1（Nrp1）是一种跨膜受体，在正常和病理性血管发育中发挥重要作用，并结合两个不同的配体家族：血管内皮生长因子（Vegf）和 3 类 semaphorin（Sema3）。尽管 Nrp1 对全身血管发育至关重要，但 Nrp1 在肺血管形态发生中的重要性尚不确定。我们假设 Sema3-Nrp1 和 Vegf-Nrp1 相互作用是肺泡化过程中肺血管发育协调的重要途径。因此，Nrp1 信号的完全缺失会导致与支气管肺发育不良发病机制相关的正常血管生成和血管成熟过程的中断。我们之前已经表明，转基因 Nrp1（Sema-）小鼠中的先天性 Sema3-Nrp1 信号缺失导致肺泡毛细血管界面形成中断和新生儿高死亡率。在这里，对 Nrp1（Sema-）幸存者在肺泡期的病理组织学检查显示出中度至重度呼吸窘迫、肺泡出血、异常扩张的毛细血管和肺泡间隔崩解，表明肺泡毛细血管界面持续不稳定。此外，与毛细血管密度降低和血管阻力增加一致，观察到高血压重塑。相比之下，尽管死亡率增加，但从出生后第 5 天开始的条件性 Nrp1 缺失对肺泡和血管发育或肺细胞分化仅有短暂影响。我们的研究结果表明，尽管 Sema3-Nrp1 信号在胎儿肺发育过程中至关重要，但 Nrp1 信号似乎不是出生后肺泡发育或血管功能所必需的。
