Pencovich N, Hantisteanu S, Hallak M, Fainaru O
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.
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.
Eur J Obstet Gynecol Reprod Biol. 2014 Aug;179:75-82. doi: 10.1016/j.ejogrb.2014.05.025. Epub 2014 Jun 2.
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.
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.
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.
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.
卵巢过度刺激综合征与血管生成增加和血管渗漏有关。在小鼠和人类的多种疾病模型中，未成熟髓样细胞（IMCs）和树突状细胞已被证明积极参与血管生成。然而，关于这些细胞在卵巢中的作用知之甚少。因此，本研究旨在确定在小鼠模型中，这些卵巢髓样细胞群体的改变是否与促性腺激素刺激有关。
将4周龄的青春期前C57Bl/6雌性小鼠分为三组：高剂量刺激组（n = 4；孕马血清促性腺激素（PMSG）20U，持续2天）、低剂量刺激组（n = 5；PMSG 5U，持续1天）和假手术对照组（n = 4）。在第3天注射人绒毛膜促性腺激素5U，并在第5天处死小鼠。通过流式细胞术、共聚焦显微镜和定量聚合酶链反应分析卵巢。
促性腺激素刺激增加了卵巢髓样细胞中CD11b(+)Gr1(+) IMCs的比例：高剂量组为22.6±8.1%，低剂量组为7.2±1.6%，对照组为4.1±0.3%（p = 0.02）。相反，促性腺激素刺激降低了卵巢CD11c(+)MHCII(+)树突状细胞的比例：高剂量组为15.1±1.9%，低剂量组为20.7±4.8%，对照组为27.3±8.2%（p = 0.02）。与树突状细胞不同，IMCs定位于PECAM1(+)内皮细胞附近。最后，促性腺激素刺激与S100A8、S100A9、Vcan和Dmbt1的表达增加以及MMP12的表达降低有关。
促性腺激素刺激与促血管生成的髓样细胞改变有关，表现为卵巢IMCs的剂量依赖性增加和树突状细胞的相应减少。募集的IMCs策略性地定位于血管生成部位。这些变化与关键促血管生成基因的差异表达有关。
