Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production.
Vascular endothelial growth factor (VEGF) displays neurotrophic and neuroprotective activities, but the mechanisms underlying these effects have not been defined. Neuropilin-1 (NP-1) is a receptor for VEGF165 and placental growth factor-2 (PlGF-2), but the role of NP-1 in VEGF-dependent neurotrophic actions is unclear. Dorsal root ganglion (DRG) neurons expressed high levels of NP-1 mRNA and protein, much lower levels of KDR, and no detectable Flt-1. VEGF165 and PlGF-2 promoted DRG growth cone formation with an effect similar to that of nerve growth factor, whereas the Flt-1-specific ligand, PlGF-1, and the KDR/Flt-4 ligand, VEGF-D, had no effect. The chemorepellent NP-1 ligand, semaphorin 3A, antagonized the response to VEGF and PlGF-2. The specific KDR inhibitor, SU5614, did not affect the anti-chemorepellent effects of VEGF and PlGF-2, whereas a novel, specific antagonist of VEGF binding to NP-1, called EG3287, prevented inhibition of growth cone collapse. VEGF stimulated prostacyclin and prostaglandin E2 production in DRG cultures that was blocked by inhibitors of cyclooxygenases; the anti-chemorepellent activities of VEGF and PlGF-2 were abrogated by cyclooxygenase inhibitors, and a variety of prostacyclin analogues and prostaglandins strikingly inhibited growth cone collapse. These findings support a specific role for NP-1 in mediating neurotrophic actions of VEGF family members and also identify a novel role for prostanoids in the inhibition of neuronal chemorepulsion.
Cheng
Lili
L
Department of Medicine, The Rayne Institute, University College London, 5 University Street, London WC1E 6JJ, United Kingdom.
Jia
Haiyan
H
Löhr
Marianne
M
Bagherzadeh
Azadeh
A
Holmes
David I R
DI
Selwood
David
D
Zachary
Ian
I
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D011464:Epoprostenol / Q000378:metabolism; D005091:Exons; D005727:Ganglia, Spinal / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D039942:Neuropilin-1 / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D007211:Indoles; C000608036:PGF protein, human; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D011453:Prostaglandins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C416849:SU 5614; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D039942:Neuropilin-1; D012313:RNA; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D040301:Vascular Endothelial Growth Factor Receptor-2; D000262:Adenylyl Cyclases; D015232:Dinoprostone