血红素加氧酶在高雌激素导致子宫内膜灌注不足中的作用

The balance between proangiogenic factors and antiangiogenic factors in uterus is very importance to maintain the function of endometrium, and it also affects the development of placenta. Superphysiolobical high level of E2 has an adverse effect on the angiogenesis of endometrium in control ovarian hyperstimulation. The abnormal angiogenesis may lead to a lower blood perfusion in uterus. Heme oxygenase (HO) was found to act as a vital factor in vascular regulation. And as pointed out in previous reports, HO play a key role in the different processes related to spontaneous abortion and pre-eclampsia. Some study Hmox-1 heterozygous (+/-) mice had an abnormal placenta development, and the bias of pro- and antiangiogenic factors was towards the antiangiogenic. The behaviors were similar to the implantation endometrium in the ovarian stimulation. Thus, we proposed that the high level of E2 could impact the angiogenesis through the HO expression in endometrium. For no information exists in the literature regarding the HO affecting the endometrial blood flow, we will detect the expression of HO and angiogenesis-associated molecules in endometrial biopsies, collected on the different day of ovarian stimulation. Then the human umbilical vein endothelial cells (HUVEC) will cultured exposed to the endometrium stroma cells, and the HO and angiogenesis factors in the supernatant fluid will be studied. The antagonist or analogy of HO will be added to the culture for a more in-deep study of the effects of HO to the function and growth of endothelial cells. This study may provide some theoretical foundation to help clinicians modified the ovulation induction programmed, so they could reduce the risk of obstetric complication which caused by the abnormal placenta development, improve artificial reproductive technique security.

子宫内膜中影响血管生成各种因子间的调节对维持正常的内膜生长和胎盘形成是十分重要的。控制性促排卵中的高雌激素可导致子宫内膜血管生成异常，内膜血流灌注不足。近年来血红加氧酶（heme oxygenase，HO）作为重要的血管生长调节因子，已经证实在自发流产和妊娠高血压中发挥作用。有报道HO-1缺陷小鼠胎盘血管发育异常，蜕膜中血管生成有关因子的表达异常，人促排卵周期种植期子宫内膜有类似表现。由此推断，高雌激素也可能影响了子宫内膜HO的表达，导致低内膜血流低灌注。由于目前缺乏相关报道，本研究将对促排卵治疗不同阶段的子宫内膜进行研究，从蛋白和mRNA水平了解内膜血管生成相关因子和HO的变化；同时通过体外与人脐静脉上皮细胞株共培养，通过添加HO的拮抗剂或激动剂，进一步了解其对血管内皮细胞的影响。从而为临床改良促排卵方案，预防胎盘发育障碍导致的产科并发症，提高IVF-ET技术安全性提供理论依据。

女性的月经周期包括了卵泡的发育和子宫内膜的周期性生长和脱落。在这两个过程中，小微血管的增生都起了非常重要的作用。血红加氧酶（heme oxygenase，HO）是一种血管生长因子，雌激素能作用于血管内皮细胞促进HO分泌。在先兆子痫研究中已经发现HO参与妊娠早期胎盘的血管重塑作用。但是对控制性促排卵中超生理的高雌激素水平下HO的改变缺乏相关研究。本课题针对促排卵后子宫内膜和卵泡液中HO表达情况进行了研究。.研究1、子宫内膜HO蛋白表达：19例供精人工受精正常妇女自然排卵黄体中期子宫内膜，与13例实施长方案促排卵治疗后因卵巢过度刺激综合症风险取消移植的不孕妇女作为研究组，取卵后5-7天子宫内膜。结果发现HO-1蛋白表达于子宫内膜的上皮细胞和基质，其中主要表达于上皮细胞，内膜基质的染色强度高于上皮细胞。高雌激素组的HO-1蛋白的染色强度和密度与正常对照组相似。该结果提示高雌激素对内膜HO-1蛋白表达不产生影响。.研究2、促排卵治疗对PCOS患者卵泡液HO的检测：采用Northern blot方法分析取卵日卵泡液中颗粒细胞的HO蛋白mRNA水平。正常对照组16例，无PCOS表现，长方案+拮抗剂方案促排卵。PCOS组25例，拮抗剂方案促排卵。结果显示PCOS妇女卵巢颗粒细胞中HO的表达改变主要以HO-2为主，主要表现为HO-2表达和合成下降（HO-2mRNA:1.15 ±0.07vs 1.55 ± 0.20，P<0.05）。为证实PCOS的慢性炎症机制提供了新的理论依据。.除此之外，针对IVF治疗的临床特点，本课题对新鲜胚胎移植后14天血清HCG水平与治疗结局预后进行了比较，提出了临床用药的指导阈值，如当血清β-HCG在<45mI U/ml时继续黄体支持治疗意义不大；血清β-HCG在46-379.25mIU/ml范围内虽可继续黄体支持保胎，但要警惕异位妊娠及早期流产的发生。.而对获卵超过15个的IVF妇女FET或鲜胚移植的临床结局分析，结果发现这部分高反应妇女的FET结局，包括临床妊娠率，活产率均超过新鲜胚胎移植组（54.5% vs 42.0%，47.1% vs 36.0%）。该结果为临床决策提供了良好的依据，对获卵数比较多尤其是超过20个获卵的IVF妇女，放弃鲜胚移植，采用全胚冷冻后续实施FET可能是更好的选择。