title: I.c.v administration of an endothelin ET(B) receptor agonist stimulates vascular endothelial growth factor-A production and activates vascular endothelial growth factor receptors in rat brain.
abstract: Vascular endothelial growth factors (VEGFs), a family of angiogenic factors, are upregulated by nerve injuries. To clarify the extracellular signals involved in VEGF production in the brain, the effects of endothelins (ETs), a family of vasoconstricting peptides, were examined. I.c.v. administration of 500 pmol/d Ala(1,3,11,15)-ET-1, an ET(B) receptor agonist, increased the level of VEGF-A mRNA in the rat cerebrum, whereas those of VEGF-B, placental growth factor (PLGF), angiopoietin (ANG)-1, and ANG-2 mRNAs were not largely affected by Ala(1,3,11,15)-ET. The ET-induced increases in cerebrum VEGF-A mRNA were reduced by coadministration of 1 nmol/d BQ788, an ET(B) antagonist. Ala(1,3,11,15)-ET-1 also stimulated the production of VEGF-A proteins in the cerebrum. Immunohistochemical observations in the cerebrum of Ala(1,3,11,15)-ET-1-infused rats showed that glial fibrillary acidic protein (GFAP)-positive astrocytes had VEGF-A immunoreactivity. Neurons, microglia, and brain capillary endothelial cells in the Ala(1,3,11,15)-ET-1-infused rats did not show VEGF-A reactivity. The i.c.v. administration of Ala(1,3,11,15)-ET-1 stimulated tyrosine phosphorylations of VEGF-R1 and R2 receptors in the rat cerebrum, whereas expression levels of total VEGF-R1 and R2 proteins were not largely changed. Immunoreactivity of tyrosine-phosphorylated VEGF-R1 was selectively shown in GFAP-positive astrocytes in the cerebrum of Ala(1,3,11,15)-ET-1-infused rats. Tyrosine-phosphorylated VEGF-R2 proteins were present in astrocytes and brain capillary endothelial cells. These findings indicate that activation of brain ET(B) receptors increases production of VEGF-A and stimulates VEGF receptor signaling in the brain.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka 584-8540, Japan. koyamay@osaka-ohtani.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Koyama
authors.forename: R
authors.initials: R
authors.lastname: Nagae
authors.forename: S
authors.initials: S
authors.lastname: Tokuyama
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019332:Endothelin-1 / Q000008:administration & dosage*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B / Q000819:agonists*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor