title: The role of pigment epithelium-derived factor in the pathophysiology and treatment of ovarian hyperstimulation syndrome in mice.
abstract: BACKGROUND
  Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproduction. OHSS is induced by an ovarian release of vasoactive, angiogenic substances that results in vascular hyperpermeability, leakage, and shift of fluids from blood vessels into the extravascular space with consequent ascites and edema that are attributed to vascular endothelial growth factor (VEGF).
  
  
  OBJECTIVE
  Our objective was to examine a physiological approach for preventing and treating OHSS, based on negating the VEGF network.
  
  
  METHODS
  We used a mouse OHSS model and cultured granulosa cells.
  
  
  RESULTS
  Changes in pigment epithelium-derived factor (PEDF) and VEGF were measured by quantitative PCR and Western blot analysis. OHSS was recorded by changes in body weight and in peritoneal vascular leakage, quantified by the modified Miles vascular permeability assay.
  
  
  RESULTS
  Granulosa cells produced and secreted the anti-angiogenic factor, PEDF, in an inverse fashion to VEGF. The physiological PEDF-VEGF counterbalance was found to be impaired in the mouse OHSS model. Treatment of OHSS-induced mice with low doses of recombinant PEDF (rPEDF) alleviated OHSS signs including edema (P < .001) and vascular leakage (P < .001) and reduced the level of ovarian VEGF mRNA. Low doses of rPEDF also reduced VEGF mRNA levels in granulosa cells in vitro. However, these effects were not seen at higher doses of rPEDF, suggesting a hormetic mechanism of rPEDF action.
  
  
  CONCLUSIONS
  These observations provide a new perspective into the pathophysiology of OHSS, namely, high expression level of VEGF together with a nearly undetectable level of PEDF. A replacement therapy with rPEDF is suggested as an innovative physiological treatment for OHSS. Finally, control of the PEDF-VEGF reciprocal relationship could open new therapeutic avenues for other angiogenic-related fertility pathologies.
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Chuderland
authors.forename: Ido
authors.initials: I
authors.lastname: Ben-Ami
authors.forename: Ruth
authors.initials: R
authors.lastname: Kaplan-Kraicer
authors.forename: Hadas
authors.initials: H
authors.lastname: Grossman
authors.forename: Raphael
authors.initials: R
authors.lastname: Ron-El
authors.forename: Ruth
authors.initials: R
authors.lastname: Shalgi
mesh_terms: D000818:Animals; D001835:Body Weight; D002199:Capillary Permeability / Q000502:physiology*; D002460:Cell Line; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism*; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D016471:Ovarian Hyperstimulation Syndrome / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism*; D051381:Rats; D015843:Serpins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor