title: Vascular endothelial growth factor A (VEGF-A) decreases expression and secretion of pleiotrophin in a VEGF receptor-independent manner.
abstract: Vascular endothelial growth factor A (VEGF-A) is a key molecule in angiogenesis acting through VEGF receptors (VEGFRs), ανβ3 integrin, receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and cell surface nucleolin (NCL). Pleiotrophin (PTN) stimulates endothelial cell migration and limits the angiogenic effects of VEGF-A165 to the levels of its own effect, possibly acting as a VEGF-A165 modifier. Since PTN and VEGF-A165 share receptors and actions on endothelial cells, in the present work we studied whether and how VEGF-A165 affects PTN expression or secretion. VEGF-A165 decreased PTN mRNA and protein levels acting at the transcriptional level. Bevacizumab, a selective VEGFR2 tyrosine kinase inhibitor and down-regulation of VEGFR2 expression by siRNA did not affect this decrease, suggesting that it is VEGFR-independent. VEGF-A121 also decreased PTN mRNA and protein levels, suggesting that heparin binding of VEGF-A165 is not involved. Blockage of cell surface NCL, lack of expression or mutation of β3 integrin and down-regulation of RPTPβ/ζ abolished the inhibitory effect of VEGF-A165 on PTN expression and secretion. Down-regulation of endogenous PTN in endothelial cells enhanced VEGF-A165-induced increase in migration and tube formation on matrigel. Collectively, these data suggest that VEGF-A down-regulates PTN expression and secretion through the RPTPβ/ζ-ανβ3-NCL axis to enhance its own effect on cell migration and further highlight the role of RPTPβ/ζ in VEGF-A actions.
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Greece; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Poimenidi
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Theodoropoulou
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Greece.
authors.forename: Marina
authors.initials: M
authors.lastname: Koutsioumpa
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Greece.
authors.forename: Lamprini
authors.initials: L
authors.lastname: Skondra
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Greece.
authors.forename: Eirini
authors.initials: E
authors.lastname: Droggiti
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; A-Skin BV, Amsterdam, The Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: van den Broek
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Koolwijk
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Greece. Electronic address: epapad@upatras.gr.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Papadimitriou
mesh_terms: D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology; D015153:Blotting, Western; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003412:Cricetulus; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008024:Ligands; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000187:drug effects; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D008024:Ligands; D010446:Peptide Fragments; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C511613:vascular endothelial growth factor A (138-165); C066845:pleiotrophin; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5
keywords: Angiogenesis; Endothelial cells; Growth factors; Migration; Nucleolin; Receptor protein tyrosine phosphatase beta/zeta