Increasing evidence suggests that normal pulmonary vascular morphogenesis is critical for the formation and maintenance of the lung parenchyma, both pre- and postnatally. Indeed, the disruption of angiogenic pathways, whether through inherent genetic predisposition or as a consequence of life-saving interventions, may underlie many pulmonary diseases of infancy, including alveolar capillary dysplasia (ACD) and bronchopulmonary dysplasia (BPD). To understand the etiology of – and advance treatments for – such diseases, we must first identify the fundamental genetic regulators that orchestrate normal parenchymal development.
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 VEGF-NRP1 interactions in systemic vascular development have been described, the importance of SEMA3-NRP1 signalling in systemic or pulmonary vascular morphogenesis is uncertain. We hypothesized that SEMA3-NRP1 and VEGF-NRP1 interactions are fundamental pathways in the orchestration of pulmonary vascular development in both the embryo and neonate. Disruption of these pathways would therefore lead to significant interruption of normal angiogenic and vascular maturation processes that are relevant to the pathogenesis of pulmonary diseases.
Using extensive histopathological analyses of NRP1 loss-of-function mice, we show evidence of a significant role for SEMA3-NRP1 signalling in fetal microvascular development: congenital loss of SEMA3-NRP1 signalling resulted in severely attenuated development of the distal vasculature and alveolar-capillary interface, leading to fatal respiratory distress at birth that is reminiscent of clinical ACD. By contrast, VEGF-NRP1 and SEMA3-NRP1 signalling appear unessential for normal alveolar and vascular development in the postnatal period, per se, despite increased mortality.
Our results demonstrate the critical involvement of SEMA3-NRP1 signalling in endothelial development and substantiate the idea that NRP1 mediates opposing and cooperative functions between SEMA3 and VEGF ligands.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/34070 |
| Date | 13 December 2012 |
| Creators | Joza, Stephen Alexander Paul |
| Contributors | Post, Martin |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0018 seconds