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Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular repair responses and angiogenesis

Chen, Yihong LU ; Gialeli, Chrysostomi LU ; Shen, Junyan LU ; Dunér, Pontus LU ; Walse, Björn LU ; Duelli, Annette ; Caing-Carlsson, Rhawnie ; Blom, Anna M LU orcid ; Zibert, John R and Nilsson, Anna Hultgårdh LU , et al. (2024) In Pharmacological Research 205.
Abstract

The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by... (More)

The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.

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publication status
published
subject
keywords
Neuropilin-1/metabolism, Humans, Human Umbilical Vein Endothelial Cells/drug effects, Animals, Neovascularization, Physiologic/drug effects, Osteopontin/metabolism, Cell Movement/drug effects, Vascular Endothelial Growth Factor Receptor-2/metabolism, Cell Proliferation/drug effects, Myocytes, Smooth Muscle/drug effects, Male, Peptides/pharmacology, Vascular Endothelial Growth Factor A/metabolism, Apoptosis/drug effects, Mice, Inbred C57BL, Protein Binding, Ischemia/drug therapy, Mice, Angiogenesis
in
Pharmacological Research
volume
205
article number
107259
pages
18 pages
publisher
Academic Press
external identifiers
  • scopus:85195874479
  • pmid:38871237
ISSN
1096-1186
DOI
10.1016/j.phrs.2024.107259
language
English
LU publication?
yes
additional info
Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.
id
28b238c0-37e0-4e10-872f-12ba079de9b3
date added to LUP
2024-07-05 14:14:12
date last changed
2025-05-11 09:40:59
@article{28b238c0-37e0-4e10-872f-12ba079de9b3,
  abstract     = {{<p>The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.</p>}},
  author       = {{Chen, Yihong and Gialeli, Chrysostomi and Shen, Junyan and Dunér, Pontus and Walse, Björn and Duelli, Annette and Caing-Carlsson, Rhawnie and Blom, Anna M and Zibert, John R and Nilsson, Anna Hultgårdh and Alenfall, Jan and Liang, Chun and Nilsson, Jan}},
  issn         = {{1096-1186}},
  keywords     = {{Neuropilin-1/metabolism; Humans; Human Umbilical Vein Endothelial Cells/drug effects; Animals; Neovascularization, Physiologic/drug effects; Osteopontin/metabolism; Cell Movement/drug effects; Vascular Endothelial Growth Factor Receptor-2/metabolism; Cell Proliferation/drug effects; Myocytes, Smooth Muscle/drug effects; Male; Peptides/pharmacology; Vascular Endothelial Growth Factor A/metabolism; Apoptosis/drug effects; Mice, Inbred C57BL; Protein Binding; Ischemia/drug therapy; Mice; Angiogenesis}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{Academic Press}},
  series       = {{Pharmacological Research}},
  title        = {{Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular repair responses and angiogenesis}},
  url          = {{http://dx.doi.org/10.1016/j.phrs.2024.107259}},
  doi          = {{10.1016/j.phrs.2024.107259}},
  volume       = {{205}},
  year         = {{2024}},
}