title: Vascular endothelial growth factor C acts as a neurotrophic factor for dopamine neurons in vitro and in vivo.
abstract: Neurotrophic factors regulate the development and maintenance of the nervous system and protect and repair dopaminergic neurons in animal models of Parkinson's disease (PD). Vascular endothelial growth factors A (VEGF-A) and B have also neurotrophic effects on various types of neurons, including dopaminergic neurons. We examined the ability of the key lymphangiogenic factor VEGF-C to protect dopaminergic cells in vitro and in vivo. The study was initiated by a finding from microarray profiling of Neuro2A-20 cells which revealed up-regulation of VEGF-C by glial cell-line-derived neurotrophic factor (GDNF). Next, we observed that VEGF-C can rescue embryonic dopaminergic neurons and activate the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) pathway in vivo. VEGF receptors 1-2 and co-receptors, neuropilins 1-2, were expressed both in mouse embryonic cultures and adult midbrains. In vivo, VEGF-C had a robust functional effect in the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD and there was a small additive effect on the survival of tyrosine hydroxylase (TH)-positive cells with GDNF. The neuroprotective effect of VEGF-C is most likely due to a combination of direct and indirect neurotrophic effects because, VEGF-C, unlike GDNF, induced also angiogenesis in the striatum following 6-OHDA insult as it did in human umbilical vein endothelial cells (HUVEC). However, we detected activation of astroglia and microglia as well as blood-brain barrier disruption after intracerebral delivery of VEGF-C, raising a concern of its safe usage as a therapeutic molecule. Our results provide evidence of VEGF-C as a neurotrophic factor that influences the dopaminergic system through multiple mechanisms.
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmacy, Viikinkaari 5E (P.O. Box 56), 00014 University of Helsinki, Finland. marjo.piltonen@helsinki.fi
authors.forename: M
authors.initials: M
authors.lastname: Piltonen
authors.forename: A
authors.initials: A
authors.lastname: Planken
authors.forename: O
authors.initials: O
authors.lastname: Leskelä
authors.forename: T T
authors.initials: TT
authors.lastname: Myöhänen
authors.forename: A-L
authors.initials: AL
authors.lastname: Hänninen
authors.forename: P
authors.initials: P
authors.lastname: Auvinen
authors.forename: K
authors.initials: K
authors.lastname: Alitalo
authors.forename: J-O
authors.initials: JO
authors.lastname: Andressoo
authors.forename: M
authors.initials: M
authors.lastname: Saarma
authors.forename: P T
authors.initials: PT
authors.lastname: Männistö
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D004298:Dopamine / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
chemical_list: D009414:Nerve Growth Factors; D042582:Vascular Endothelial Growth Factor C; D004298:Dopamine