title: Signal mechanisms of vascular endothelial growth factor and interleukin-8 in ovarian hyperstimulation syndrome: dopamine targets their common pathways.
abstract: BACKGROUND
  Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian stimulation with massive ascites, pleural effusion and hemoconcentration. The pathophysiological signal mechanisms of OHSS are still unclear and merit further investigation.
  
  
  METHODS
  Various angiogenic cytokines of follicular fluid and ascites of patients with risk of OHSS were measured, and examined for inducing endothelial permeability. These include vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, basic fibroblast growth factor, tumor necrosis factor-alpha, IL-1alpha, IL-1beta and platelet-derived growth factor. We explore the molecular signal pathways of major contributing cytokines in granulosa-lutein cells and endothelial cells possibly involved in OHSS.
  
  
  RESULTS
  Neutralizing antibodies of VEGF or IL-8 significantly decreased follicular fluid- and ascites-induced endothelial permeability. Human chorionic gonadotrophin induced VEGF secretion of granulosa-lutein cells through the Sp1 and CREB dependent pathways. IL-8 activated CXCR1/2 of endothelial cells leading to VEGF receptor (VEGFR)-2 transactivation. Both VEGF and IL-8 of follicular fluid enhanced endothelial permeability via VEGFR-2-mediated Rho/Rock activation, actin polymerization and phosphorylations of VE-cadherin and occludin, resulting in opening of adherens junctions and tight junctions. Dopamine (2 microM) inhibited follicular fluid-induced VEGFR-2 signals and endothelial permeability, without diminishing migration and tube formation.
  
  
  CONCLUSIONS
  Our results suggest that VEGF and IL-8 secreted from corpora luteae may play major roles in OHSS. Delineation of signal pathways would be helpful for treatment. Dopamine may block VEGF- and IL-8-induced endothelial permeability by inhibiting common VEGFR-2 dependent signals.
authors.affiliation: Department of Obstetrics and Gynecology, National Taiwan University, No 7 Chung-Shan South Road, Taipei, Taiwan.
authors.forename: Shee-Uan
authors.initials: SU
authors.lastname: Chen
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Chou
authors.forename: Chung-Wu
authors.initials: CW
authors.lastname: Lin
authors.forename: Hsinyu
authors.initials: H
authors.lastname: Lee
authors.forename: Jiahn-Chun
authors.initials: JC
authors.lastname: Wu
authors.forename: Hsin-Fen
authors.initials: HF
authors.lastname: Lu
authors.forename: Chin-Der
authors.initials: CD
authors.lastname: Chen
authors.forename: Yu-Shih
authors.initials: YS
authors.lastname: Yang
mesh_terms: D000199:Actins / Q000378:metabolism; D001201:Ascites / Q000503:physiopathology; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D015571:Follicular Fluid / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology / Q000502:physiology*; D008184:Luteal Cells / Q000276:immunology; D016471:Ovarian Hyperstimulation Syndrome / Q000503:physiopathology*; D010539:Permeability / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
chemical_list: D000199:Actins; D006063:Chorionic Gonadotropin; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D004298:Dopamine