title: Gonadotropin stimulation in mice leads to ovarian accumulation of immature myeloid cells and altered expression of proangiogenic genes.
abstract: OBJECTIVE
  Ovarian hyperstimulation syndrome is associated with increased angiogenesis and vascular leakage. Immature myeloid cells (IMCs) and dendritic cells have been shown to be actively involved in angiogenesis in several disease models in mice and humans. Nevertheless, little is known about the role of these cells in the ovary. As such, this study sought to determine whether alterations in these ovarian myeloid cell populations are associated with gonadotropin stimulation in a mouse model.
  
  
  METHODS
  Four-week-old pre-pubertal C57Bl/6 female mice were allocated into three groups: high-dose stimulation (n=4; pregnant mare serum gonadotropins (PMSG) 20U for 2 days), low-dose stimulation (n=5; PMSG 5U for 1 day) and sham-treated controls (n=4). Human chorionic gonadotropin 5U was injected on Day 3, and the mice were killed on Day 5. Ovaries were analysed by flow cytometry, confocal microscopy and quantitative polymerase chain reaction.
  
  
  RESULTS
  Gonadotropin stimulation increased the proportion of CD11b(+)Gr1(+) IMCs among the ovarian myeloid cells: 22.6±8.1% (high dose), 7.2±1.6% (low dose) and 4.1±0.3% (control) (p=0.02). Conversely, gonadotropin stimulation decreased the proportion of ovarian CD11c(+)MHCII(+) dendritic cells: 15.1±1.9% (high dose), 20.7±4.8% (low dose) and 27.3±8.2% (control) (p=0.02). IMCs, unlike dendritic cells, were localized adjacent to PECAM1(+) endothelial cells. Finally, gonadotropin stimulation was associated with increased expression of S100A8, S100A9, Vcan and Dmbt1, and decreased expression of MMP12.
  
  
  CONCLUSIONS
  Gonadotropin stimulation is associated with proangiogenic myeloid cell alterations, reflected by a dose-dependent increase in ovarian IMCs and a parallel decrease in dendritic cells. Recruited IMCs localize strategically at sites of angiogenesis. These changes are associated with differential expression of key proangiogenic genes.
authors: Laboratory for Reproductive Immunology, Department of Obstetrics and Gynaecology, Hillel Yaffe Medical Centre, Faculty of Medicine, Technion, Israel Institute of Technology, Hadera, Israel; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; Department of Surgery, Tel Aviv Souraski Medical Center, Tel Aviv, Israel.
authors: N
authors: N
authors: Pencovich
authors: Laboratory for Reproductive Immunology, Department of Obstetrics and Gynaecology, Hillel Yaffe Medical Centre, Faculty of Medicine, Technion, Israel Institute of Technology, Hadera, Israel; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors: S
authors: S
authors: Hantisteanu
authors: Laboratory for Reproductive Immunology, Department of Obstetrics and Gynaecology, Hillel Yaffe Medical Centre, Faculty of Medicine, Technion, Israel Institute of Technology, Hadera, Israel.
authors: M
authors: M
authors: Hallak
authors: Laboratory for Reproductive Immunology, Department of Obstetrics and Gynaecology, Hillel Yaffe Medical Centre, Faculty of Medicine, Technion, Israel Institute of Technology, Hadera, Israel; Department of Surgery, Tel Aviv Souraski Medical Center, Tel Aviv, Israel; IVF Unit, Department of Obstetrics and Gynaecology, Hillel Yaffe Medical Centre, Faculty of Medicine, Technion, Israel Institute of Technology, Hadera, Israel. Electronic address: ofainaru@techunix.technion.ac.il.
authors: O
authors: O
authors: Fainaru
mesh_terms: D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D005260:Female; D006064:Gonadotropins, Equine / Q000494:pharmacology*; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D010053:Ovary / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D006063:Chorionic Gonadotropin; D006064:Gonadotropins, Equine
keywords: Angiogenesis; Dendritic cells; Immature myeloid cells; Ovarian stimulation