Abstract
Neuropilin 1 (NRP1) is important for neuronal and cardiovascular development due to its role in conveying class 3 semaphorin and vascular endothelial growth factor signaling, respectively. NRP1 is expressed in smooth muscle cells (SMCs) and mediates their migration and proliferation in cell culture and is implicated in pathological SMC remodeling in vivo. To address the importance of Nrp1 for SMC function during development, we generated conditional inducible Nrp1 SMC-specific knockout mice. Induction of early postnatal SMC-specific Nrp1 knockout led to pulmonary hemorrhage associated with defects in alveogenesis and revealed a specific requirement for Nrp1 in myofibroblast recruitment to the alveolar septae and PDGF-AA-induced migration in vitro. Furthermore, SMC-specific Nrp1 knockout inhibited PDGF-BB-stimulated SMC outgrowth ex vivo in aortic ring assays and reduced pathological arterial neointima formation in vivo. In contrast, we observed little significant effect of SMC-specific Nrp1 knockout on neonatal retinal vascularization. Our results point to a requirement of Nrp1 in vascular smooth muscle and myofibroblast function in vivo, which may have relevance for postnatal lung development and for pathologies characterized by excessive SMC and/or myofibroblast proliferation.
Highlights
Neuropilin-1 (NRP1) is a transmembrane glycoprotein receptor essential for both vascular and neuronal development due to its role in mediating vascular endothelial growth factor (VEGF) and class 3 semaphorin signaling, respectively [14, 16, 25, 36]
Nrp1 allele recombination and protein knockdown in smooth muscle cells (SMCs) were confirmed by genotyping PCR (Fig. 1C) and immunostaining (Fig. 1D)
The Nrp1SMCiKO neonates appeared viable and healthy compared with their littermate controls; internal examination revealed hemorrhaging in the lungs of the Nrp1SMCiKO neonatal pups from P8 (Fig. 2A)
Summary
Neuropilin-1 (NRP1) is a transmembrane glycoprotein receptor essential for both vascular and neuronal development due to its role in mediating vascular endothelial growth factor (VEGF) and class 3 semaphorin signaling, respectively [14, 16, 25, 36]. Several studies have reported NRP1 expression in smooth muscle cells (SMCs) and revealed an important role for NRP1 in vascular SMC migration [13, 27, 30, 35]. The lack of an overt phenotype in constitutively SMC-specific Nrp1-null mice could be indicative of genetic redundancy, as reported for other constitutive knockout mice [5, 17, 42]. Nrp compensates for loss of semaphorin binding to NRP1 in Nrp1Sema/Sema mice [15] These data suggest a partial genetic redundancy between Nrp and Nrp, which could explain the lack of an overt phenotype in constitutive SMC-specific Nrp1null mice. Nrp was necessary for pathological neointima formation in vivo, for PDGF-BB-induced SMC outgrowth ex vivo in aortic rings, and for PDGF-AA-induced pulmonary myofibroblast migration in cultured cells
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