title: 15-lipoxygenase-1 prevents vascular endothelial growth factor A- and placental growth factor-induced angiogenic effects in rabbit skeletal muscles via reduction in growth factor mRNA levels, NO bioactivity, and downregulation of VEGF receptor 2 expression.
abstract: Human 15-lipoxygenase-1 (15-LO-1) is an oxidizing enzyme capable of producing reactive lipid hydroperoxides. 15-LO-1 and its products have been suggested to be involved in many pathological conditions, such as inflammation, atherogenesis, and carcinogenesis. We used adenovirus-mediated gene transfers to study the effects of 15-LO-1 on vascular endothelial growth factor (VEGF)-A165- and placental growth factor (PlGF)-induced angiogenesis in rabbit skeletal muscles. 15-LO-1 significantly decreased all angiogenic effects induced by these growth factors, including capillary perfusion, vascular permeability, vasodilatation, and an increase in capillary number. The effects are attributable to the reduction in the amount of VEGF-A165 and PlGF transcripts by 15-LO-1, resulting in reduced protein expression. The most likely mediator of the VEGF family-induced capillary vasodilatation is nitric oxide (NO), which is produced by NO synthases. Endothelial NO synthase protein expression and NO synthase activity were significantly induced by VEGF-A165, and these inductions were reduced by 15-LO-1. VEGF-A165 induces its angiogenic effects primarily via vascular endothelial growth factor receptor (VEGFR)2, and also PlGF mediates angiogenic signaling via VEGFR2, even though it binds to VEGFR1. VEGFR2 expression is induced by peroxisome proliferator-activating receptor . We showed by quantitative RT-PCR and immunohistochemistry that expression of endogenous rabbit peroxisome proliferator-activating receptor and VEGFR2 were significantly increased in the growth factor-transduced muscles, but these inductions were efficiently prevented by 15-LO-1. In conclusion, the results suggest that expression of 15-LO-1 has an efficient antiangiogenic effect in vivo via reduction in growth factor mRNA levels, NO bioactivity, and VEGFR2 expression.
authors.affiliation: Department of Biotechnology and Molecular Medicine, University of Kuopio, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Viita
authors.forename: Johanna
authors.initials: J
authors.lastname: Markkanen
authors.forename: Emmi
authors.initials: E
authors.lastname: Eriksson
authors.forename: Markku
authors.initials: M
authors.lastname: Nurminen
authors.forename: Kati
authors.initials: K
authors.lastname: Kinnunen
authors.forename: Mohan
authors.initials: M
authors.lastname: Babu
authors.forename: Tommi
authors.initials: T
authors.lastname: Heikura
authors.forename: Sanna
authors.initials: S
authors.lastname: Turpeinen
authors.forename: Svetlana
authors.initials: S
authors.lastname: Laidinen
authors.forename: Teemu
authors.initials: T
authors.lastname: Takalo
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000097:blood; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D009569:Nitric Oxide; D001093:Arachidonate 15-Lipoxygenase; D040301:Vascular Endothelial Growth Factor Receptor-2