Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation
Multiple paths to leaky blood vessels - The endothelial cells that line blood vessels act as a barrier between the blood and many tissues in the body. Blood vessels that are excessively leaky can lead to fluid buildup in tissues and promote the inappropriate movement of cells, such as the metastasis...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
26 April 2016
|
| In: |
Science signaling
Year: 2016, Volume: 9, Issue: 425 |
| ISSN: | 1937-9145 |
| DOI: | 10.1126/scisignal.aad3812 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1126/scisignal.aad3812 Verlag, Volltext: https://stke.sciencemag.org/content/9/425/ra42 
|
| Author Notes: | Lise Roth, Claudia Prahst, Tina Ruckdeschel, Soniya Savant, Simone Weström, Alessandro Fantin, Maria Riedel, Mélanie Héroult, Christiana Ruhrberg, and Hellmut G. Augustin |
| Summary: | Multiple paths to leaky blood vessels - The endothelial cells that line blood vessels act as a barrier between the blood and many tissues in the body. Blood vessels that are excessively leaky can lead to fluid buildup in tissues and promote the inappropriate movement of cells, such as the metastasis of cancer cells into the blood. The binding of VEGF (vascular endothelial cell growth factor) to its receptor VEGFR-2 enhances vascular permeability. Roth et al. discovered that different ligands that bound and triggered the clustering of VEGF coreceptor NRP1 increased vascular permeability without involving VEGFR-2 activation. In mice that expressed a form of NRP1 lacking the cytoplasmic domain, the NRP1-clustering stimuli did not enhance leakage from blood vessels. Thus, understanding how the cytoplasmic domain of NRP1 mediates increased vascular permeability may lead to new targets for preventing this condition. - Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165-amino acid isoform of vascular endothelial growth factor A (VEGF-A165). NRP1 is also the receptor for the CendR peptides, a class of cell- and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors. We report here that the NRP1 intracellular domain mediates vascular permeability. Stimulation with VEGF-A165, a ligand-blocking antibody, and a CendR peptide led to NRP1 accumulation at cell-cell contacts in endothelial cell monolayers, increased cellular permeability in vitro and vascular leakage in vivo. Biochemical analyses, VEGF receptor-2 (VEGFR-2) silencing, and the use of a specific VEGFR blocker established that the effects induced by the CendR peptide and the antibody were independent of VEGFR-2. Moreover, leakage assays in mice expressing a mutant NRP1 lacking the cytoplasmic domain revealed that this domain was required for NRP1-induced vascular permeability in vivo. Hence, these data define a vascular permeability pathway mediated by NRP1 but independent of VEGFR-2 activation. - Blood vessel leakiness can be induced through the co-receptor NRP1 independently of VEGFR. - Blood vessel leakiness can be induced through the co-receptor NRP1 independently of VEGFR. |
|---|---|
| Item Description: | Gesehen am 23.04.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1937-9145 |
| DOI: | 10.1126/scisignal.aad3812 |