2-甲氧雌二醇对子痫前期血管内皮细胞损伤的作用研究

Preeclampsia (PE) is a specific complication of pregnancy characterized by general endothelium dysfunction. Kalluri et al firstly reported that pregnant mice deficient in 2-methoxyestradiol (2ME) showed a PE-like phenotype; 2ME ameliorated all the symptoms in the mice. But its mechanism remains unclear. ..Our previous results showed plasma 2ME correlated positively with plasma nitride oxide and negatively with plasma endothelin-1. This proved that 2ME correlates with the degree of endothelium dysfunction...At the aim of proving that 2ME can restore endothelium dysfunction, now we will build a dysfunctional model of human uterine microvascular endothelial cells(HUtMEC) by culturing theses cells in hypoxia-reoxygenation conditions or with H2O2 incubation. The effects of 2ME on this model will be detected. Then we will measure the effects of 2ME on vasoconstriction and vasodilation of the vessels dissected from myometrium of PE patients by wire myography. To elucidate the molecular mechanism of 2ME's effects on endothelium dysfunction, we will study the role of NFκB on recovery of HUtMEC oxidative stress dysfunction by 2ME. ..In this study, we explore the relationship between 2ME and endothelium dysfunction in PE for the first time. It suggests a new mechanism of 2ME's amelioration of PE, and will provide evidences for developing a new therapy for PE.

子痫前期（PE）是孕期特有的并发症，全身血管内皮损伤是其病理生理基础。Kalluri等通过基因敲除方法首次制造了2甲氧雌二醇（2ME）产生缺陷的PE小鼠模型，补充2ME能改善其临床症状，但具体机制不明。.我们前期研究发现，PE患者的血浆2ME水平明显下降，且与血浆一氧化氮呈正相关、与内皮素-1呈负相关，表明2ME与血管内皮损伤相关。.本课题将建立缺氧-复氧或过氧化氢诱导人子宫微血管内皮细胞株（HUtMEC）损伤模型，检测2ME对其损伤是否有修复能力。我们还将用先进的微血管张力检测仪进一步验证2ME对PE患者离体子宫微血管中在位血管内皮细胞的修复功能。最后，我们将研究NFκB在2ME缓解HUtMEC氧化应激损伤中的作用，阐明2ME修复血管内皮损伤的分子机制。.本课题首次探讨2ME与PE血管内皮损伤的关系，提出2ME缓解PE症状的新假说并尝试阐明其机制，将为探索治疗PE的新方法提供实验依据。

子痫前期(PE)是孕期特有的并发症,全身血管内皮损伤是其病理生理基础。以往的研究发现，2甲氧雌二醇(2ME)产生缺陷的小鼠可产生PE样表型,补充2ME能改善小鼠的临床症状,但具体机制不明。. 本研究发现,早发型重度PE患者的血浆2ME水平明显下降，且患者的血浆2ME水平与其收缩压、舒张压和平均动脉压呈显著负相关，2ME水平低下是子痫前期病人高血压的独立相关因素。. 我们通过分离人离体子宫肌层微动脉,用微血管张力仪测定2ME对离体子宫微动脉舒缩功能的影响,发现2ME对于离体人类子宫肌层微血管具有短效及长效的促血管扩张作用,而且短效及长效作用均是NO依赖性的，与子宫微血管内皮细胞功能完整性有关。. 在此基础上，我们又首次发现2ME能通过调节人子宫微血管内皮细胞株（UTMVEC细胞）分泌NO、PGI2、ET1和TXA2来调控血管的舒缩功能，且这些调控又依赖NO合成酶发挥作用。. 最后，我们通过建立TNFα诱导UTMVEC细胞损伤模型，在国内外首次发现，2ME可以抑制TNFα诱导的UTMVEC细胞损伤后表达粘附分子ICAM-1和VCAM-1；2ME还可以使TNFα诱导的NF-κB表达、IKKs/IκBα信号通路活化得到抑制。证明了2ME可通过调节NF-κB／IKKs/IκBα信号通路抑制ICAM-1和VCAM-1的表达，从而改善血管内皮细胞损伤。. 我们的研究在国内外首次从2ME参与人类子宫微血管舒缩调节及血管内皮损伤修复的角度，揭示子痫前期新的病理生理机制，为探索治疗子痫前期的可能新方法提供了实验室依据。