The Dual Role of PEDF in the Pathogenesis of OHSS: Negating Both Angiogenic and Inflammatory Pathways.
Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproductive technologies. This complex syndrome is known to involve massive angiogenesis and inflammation. We have previously established the anti-angiogenic involvement of pigment epithelium-derived factor (PEDF) in the pathophysiology and treatment of OHSS.



Evaluate the anti-inflammatory role of PEDF in OHSS.



In vivo mouse OHSS model and in vitro cultures of granulosa cells.



Changes in the expression of PEDF, IL-6, IL-8, and vascular endothelial growth factor (VEGF) were measured by quantitative PCR and ELISA; OHSS symptoms were recorded (body and ovarian weight gain and peritoneal vascular leakage quantified by the modified Miles's assay).



Rat granulosa cell-line stimulated with lysophosphatidic acid (LPA), exhibited a significant increase in IL-6 expression, concomitantly with a decrease in PEDF level (P < .01). Co-stimulation with recombinant PEDF (rPEDF) decreased the expression of IL-6 significantly (P < .05). Furthermore, the expression of IL-6 and IL-8 increased in LPA-stimulated human primary granulosa cells (P < .01). Co-stimulation with rPEDF decreased the expression of LPA-induced IL-6 and IL-8 mRNA and protein by 4- and 2- to 5-fold, respectively. IL-8-stimulated human primary granulosa cells exhibited increased expression of VEGF mRNA; co-stimulation with hCG induced a significantly higher increase in the expression of VEGF mRNA (P < .001), which was counteracted by rPEDF. Subcutaneous injection of 0.5 mg/kg rPEDF to OHSS-induced mice reduced the increased expression of IL-6 in the ovary (P < .01) and alleviated the severity of all OHSS parameters.



Our findings provide a framework that correlates down-regulation of OHSS symptoms caused by PEDF with both angiogenic and inflammatory pathways.
Department of Cell and Developmental Biology (I.M., D.C., H.G., R.S.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
Irit
I
Miller
Department of Cell and Developmental Biology (I.M., D.C., H.G., R.S.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
Dana
D
Chuderland
Department of Cell and Developmental Biology (I.M., D.C., H.G., R.S.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
Hadas
H
Grossman
Department of Cell and Developmental Biology (I.M., D.C., H.G., R.S.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
Raphael
R
Ron-El
Department of Cell and Developmental Biology (I.M., D.C., H.G., R.S.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
Ido
I
Ben-Ami
Department of Cell and Developmental Biology (I.M., D.C., H.G., R.S.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
Ruth
R
Shalgi
D000328:Adult; D000818:Animals; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000378:metabolism*; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*; D016471:Ovarian Hyperstimulation Syndrome / Q000378:metabolism*; D051381:Rats; D015843:Serpins / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D055815:Young Adult; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D009414:Nerve Growth Factors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor