The differences of mechanisms between normal luteal formation and occurrence of ovarian hyperstimulation syndrome

正常黄体形成与卵巢过度刺激综合征发生机制的差异

• 批准号: 14571574
• 负责人: ENDO Toshiaki
• 金额: $ 2.56万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571574/
• 关键词: corous Luteum; ovarian hyperstimulation syndrome; vascular permeability; vascular endothelial growth factor; tight junction; claudin-5; occludin; 血管新生

Vascular endothelial growth factor(VEGF) is well known to stimulate both the growth of endothelium and vascular permeability. VEGF expression in the ovary is also reported to increase during normal luteal formation. In this study we investigated the mechanisms of the occurrence of ovarian hyperstimulation syndrome(OHSS).The expression of VEGE and VEGF receptors(R) was extremely stimulated in the ovaries of OHSS rat models compared with corpora lutea of pseudopregnant rats. Vascular permeability examined with Evans blue was markedly increased in the ovaries of OHSS rats. Gonadotropin releasing hormone agonist(GnRHa) treatment blocked the increase of VEGF-VEGFR expression and vascular permeability of the ovaries of OHSS rats.Tight junction proteins of endothelium are reported to play a pivotal role in vascular permeability. As there are known to be several sorts of tight junction proteins, we checked the expression of such proteins in the ovaries of OHSS rats.Claudin-5 and occludin protein were significantly decreased in the ovaries OHSS rats. However, GnRHa treatment blocked the decrease in both proteins. Moreover, we clinically experienced that the continuation at GnRHa prevented the occurrence of OHSS during in vitro fertilization and embryo transfer.In summary, the decreased expression of claudin-5 and occludin caused by excess expression of VEGF-VEGFR was speculated to change from normal luteal formation into the occurrence of OHSS.

血管内皮生长因子（VEGF）是众所周知的刺激内皮细胞的生长和血管通透性。卵巢中VEGF的表达也被报道在正常黄体形成期间增加。卵巢过度刺激综合征（OHSS）大鼠模型卵巢组织中VEGE和VEGF受体（R）的表达明显高于假孕大鼠的黄体组织。伊文思蓝染色显示OHSS大鼠卵巢血管通透性明显增加。促性腺激素释放激素激动剂（GnRHa）治疗可阻断OHSS大鼠卵巢VEGF-VEGFR表达的增加和血管通透性的增加。由于紧密连接蛋白的种类繁多，我们检测了OHSS大鼠卵巢中紧密连接蛋白的表达，发现OHSS大鼠卵巢中Claudin-5和occludin蛋白表达明显降低。然而，GnRHa治疗阻断了这两种蛋白质的减少。此外，我们在临床上观察到，持续使用GnRHa可以预防体外受精-胚胎移植过程中OHSS的发生，综上所述，推测VEGF-VEGFR过度表达导致claudin-5和occludin表达降低，是正常黄体形成转变为OHSS的原因。

项目成果

Manase K., Endo T., Henmi H., Kitajima Y., Yamazaki K., Nishikawa A., Mitaka T., Sato H., Kudo R.: "The significance of membrane type 1 metalloproteinase in structural involution of human corpora lutea."Mol Hum Reprod. 8. 742-749 (2002)

Manase K.、Endo T.、Henmi H.、Kitajima Y.、Yamazaki K.、Nishikawa A.、Mitaka T.、Sato H.、Kudo R.：“膜 1 型金属蛋白酶在人类语料库结构退化中的意义

Chiba H. et al.: "Hepatocyte nuclear factor (HNF)-4alpha triggers formation of functional tight junctions and establishment of polarized epithelial morphology in F9 embryonal carcinoma cell"Exp Cell Res. 286・2. 288-297 (2003)

Chiba H.等人：“肝细胞核因子（HNF）-4α触发F9胚胎癌细胞中功能性紧密连接的形成和极化上皮形态的建立”Exp Cell Res 286・2（2003）。

Kitajima Y., et al.: "Gonadotropin-releasing hormone agonist administration reduced vascular endothelial growth factor (VEGF), VEGF receptors, and vascular permeability of the ovaries of hyperstimulated rats."Fertil Steril. 81. 842-849 (2004)

Kitajima Y. 等人：“给予促性腺激素释放激素激动剂可降低血管内皮生长因子 (VEGF)、VEGF 受体和过度刺激大鼠卵巢的血管通透性。”Fertil Steril。

Henmi H., et al.: "Effects of ascorbic acid supplementation on serum progesterone levels in patients with a luteal phase defect."Fertil Steril. 80. 459-461 (2003)

Henmi H.等人：“补充抗坏血酸对黄体期缺陷患者血清黄体酮水平的影响。”Fertil Steril。

Manase K, Endo T, et al.: "The significance of membrane type 1 metalloproteinas in structural involution of human corpora lutea"Mol Hum Reprod. 8(8). 742-749 (2002)

Manase K、Endo T 等人：“1 型膜金属蛋白在人类黄体结构退化中的重要性”Mol Hum Reprod。