Abstract
Angiogenesis relies on the ability of endothelial cells (ECs) to migrate over the extracellular matrix via integrin receptors to respond to an angiogenic stimulus. Of the two neuropilin (NRP) orthologs to be identified, both have been reported to be expressed on normal blood and lymphatic ECs, and to play roles in the formation of blood and lymphatic vascular networks during angiogenesis. Whilst the role of NRP1 and its interactions with integrins during angiogenesis has been widely studied, the role of NRP2 in ECs is poorly understood. Here we demonstrate that NRP2 promotes Rac-1 mediated EC adhesion and migration over fibronectin (FN) matrices in a mechanistically distinct fashion to NRP1, showing no dependence on β3 integrin (ITGB3) expression, or VEGF stimulation. Furthermore, we highlight evidence of a regulatory crosstalk between NRP2 and α5 integrin (ITGA5) in ECs, with NRP2 depletion eliciting an upregulation of ITGA5 expression and disruptions in ITGA5 cellular organization. Finally, we propose a mechanism whereby NRP2 promotes ITGA5 recycling in ECs; NRP2 depleted ECs were found to exhibit reduced levels of total ITGA5 subunit recycling compared to wild-type (WT) ECs. Our findings expose NRP2 as a novel angiogenic player by promoting ITGA5-mediated EC adhesion and migration on FN.
Highlights
Neuropilins (NRPs) are single non-tyrosine kinase receptors belonging to a family of type I transmembrane glycoproteins (MW ∼130–140 kDa) (Soker et al, 1998)
We reported that complete loss of the Itgb3 gene enhanced endothelial cells (ECs) permeability through the upregulation of vascular endothelial growth factor (VEGF)-VEGFR2-ERK1/2 signaling (Robinson et al, 2004), and that NRP1 and ERK1/2 expression was elevated in ITGB3-NULL ECs
We previously showed the involvement of NRP1 during VEGF-stimulated angiogenesis to be dependent upon ITGB3 in ECs (Ellison et al, 2015)
Summary
Neuropilins (NRPs) are single non-tyrosine kinase receptors belonging to a family of type I transmembrane glycoproteins (MW ∼130–140 kDa) (Soker et al, 1998). Two NRP orthologs have been identified in vertebrates, NRP1 and NRP2, both of which share a very similar domain structure and an overall 44% amino acid homology (Pellet-Many et al, 2008; Zachary, 2014) Their expression and function have been identified in many cell types, including nerve cells, endothelial cells (ECs), epithelial cells, immune cells, osteoblasts and tumor cells (Bielenberg et al, 2004; Zachary, 2014). In ECs, it is believed that NRPs play an essential role in sprouting angiogenesis and lymphogenesis through the selective binding to members of the vascular endothelial growth factor (VEGF) family. Following this complex formation, NRPs function as co-receptors with VEGFRs to enhance the VEGF-induced. In this study we aimed to investigate whether NRP2 shares a similar interaction with ITGB3 or other integrins in ECs
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