针刺对控制性促超排卵围着床期微血管形成和血流动力学的调节机制研究

The successful pregnancy of IVF-ET procedure mostly depends on the embryo implantation, while the lower implantation rate in controlled ovarian stimulation cycles is associated with the defects of endometrium angiogenesis in peri-implantation period. Our previous studies identified that acupunature could improve the implantation rate in IVF-ET through regulating the chemokines in endometroium, which could modulate the accumulation and differentiation of endometrial immune cells. However, the immune cells, especially the dendritic cells (DC) and nature killer cells (NK), also play an important role in endometrium angiogenesis. Accordingly, in this study we will combine the clinic prospective trial and animal simulation model experiments to validate our proposal that acupunature could regulate endometrium angiogenesis and blood flow through immune cells in peri-implantation period, which could be the reason why acupunature improve endometrium receptivity and embryo implantation. In clinic trail study, the effects of acupunature on the endometrium blood flow by VI,FI,VFI factors will be investigated through the 3D power Doppler ultrasound scan in controlled ovarian stimulation cycles. In the animal experiments, the effects of acupunature on micro-vascular density of peri-implantation endometrium, the NK and TC cells' accumulation,differentiation and functions will be studied. These include their secretion of angiogenesis factors (VEGF, Ang, Tie receptor,sFlt1) and the regulation of vascular endothelial cells' proliferation, migration, tube formation, et al. All together, this study will provide new proof for the benefits of the application of acupunature on assistant reproductive technology.

胚胎着床直接影响着IVF-ET的成功率，而促超排卵后的低着床率与内膜血管形成缺陷有关。前期研究表明：针灸能改善IVF-ET的着床率，其机制与内膜趋化因子调节免疫细胞聚集和分化有关。鉴于免疫细胞，尤其是树突状细胞(DC)和自然杀伤细胞(NK)，在血管形成中的作用，本研究将前瞻性随机对照临床试验和模型实验相结合，应用先进的3D能量多普勒技术观察针灸对IVF-ET促超排卵后患者围着床期子宫内膜VI、FI、VFI等血流指标的影响，同时利用促超排卵动物模型观察针灸对围着床期子宫内膜微血管密度，DC和NK的分布、表型、数量和其分泌的血管活性因子如VEGF、Ang、Tie受体等的影响，并分离子宫内膜中的DC和NK，观察其对血管内皮细胞增殖、成管活性的影响，以期证明"针灸可能通过调节内膜免疫细胞而改善血管的形成和血流灌注，从而提高子宫内膜容受性、促进胚胎着床"的假说，为针灸辅助不孕症的治疗提供依据。

胚胎着床直接影响着IVF-ET的成功率，而促超排卵后的低着床率与内膜血管形成缺陷有关。最新的3D能量多普勒超声，可利用血管化指数vascularization index (VI), 血流指数flow index (FI), 血管化-血流指数vascularization flow index (VFI)等指标来可靠地反映子宫内膜和内膜下血流状态，研究显示，在促排卵后行宫腔内人工授精的过程中，妊娠组VI、FI、VFI指数显著高于较未妊娠组，与胚胎着床密切相关，可以预测妊娠。在本随机临床对照研究中，利用先进的3D－PUA技术评估患者促超排卵后黄体期（即围着床期）子宫内膜的血流状态。本前瞻随机对照研究证实针灸治疗后，促超排卵患者黄体期子宫内膜VI、FI、VFI等血流参数均优于对照组，提示针灸治疗有改善子宫内膜血流灌注与促进微血管形成的作用。同时，针灸治疗组的患者获得了更高的妊娠率、胚胎着床率与报婴回家率，说明针灸治疗有助于改善IVF-ET的治疗结局。另一方面，我们构建了促超排卵大鼠动物模型，观察到促超排卵大鼠子宫内膜存在血管生成障碍的现象并伴随降低的妊娠率，而针灸可显著提高促排卵大鼠围着床期子宫内膜微血管密度，促进血管活性因子如VEGF、Ang、Tie受体等表达和分泌，有助于改善内膜血流并促进胚胎着床获得更佳的妊娠结局。而针灸治疗后内膜自然杀伤细胞的数量与血管活性因子的变化一致，提示该细胞可能参子宫血管形成的调节。终上所述，针灸可能通过调节内膜NK免疫细胞而改善血管的形成和血流灌注，从而提高子宫内膜容受性、促进胚胎着床。