Hyperstimulation and a gonadotropin-releasing hormone agonist modulate ovarian vascular permeability by altering expression of the tight junction protein claudin-5
Hyperstimulation and a gonadotropin-releasing hormone agonist modulate ovarian vascular permeability by altering expression of the tight junction protein claudin-5
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DOI：
10.1210/en.2005-0700
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发表时间：
2006-02-01
期刊：
影响因子：
4.8
通讯作者：
Saito, T
中科院分区：
文献类型：
--
作者：
Kitajima, Y;Endo, T;Saito, T
我们研究了 GnRH 激动剂 (GnRHa) 在卵巢过度刺激综合征 (OHSS) 大鼠模型中影响卵巢血管分布、血管通透性和紧密连接蛋白 Claudin-5 表达的机制。过度刺激的大鼠从生后第 25 天至第 28 天连续 4 天接受过量妊娠马血清促性腺激素 (PMSG；50 IU/天)，随后在第 29 天接受 25 IU 人绒毛膜促性腺激素 (hCG)。对照大鼠在生后第 27 天接受 10 IUPMSG，随后在第 29 天接受 10 IU hCG。在第29和30天（短期GnRHa治疗）或第25至30天（长期GnRHa治疗）对一些过度刺激的大鼠施用（亮丙瑞林100μg/kg.d）。通过对冯·维勒布兰德因子的分布进行免疫组织化学分析来评估卵巢血管密度（每10毫米（2）的血管数）和血管内皮面积（百分比），而血管通透性则根据伊文思蓝的渗漏来评估。高剂量的PMSG和hCG显着增加卵巢重量、血管通透性、血管密度和血管内皮面积，并显着降低claudin-5蛋白和mRNA的表达。所有这些作用均被 GnRHa 显着且剂量依赖性地抑制。这表明claudin-5表达的减少在OHSS中观察到的卵巢血管通透性增加中起着至关重要的作用，并且其表达可以通过GnRHa治疗来调节。事实上，防止内皮细胞中紧密连接蛋白的重新分布以及由此导致的内皮屏障结构的丧失可能是保护患者免受 OHSS 病例中大量血管外液体积聚的关键。
We investigated the mechanism by which a GnRH agonist (GnRHa) affects ovarian vascularity, vascular permeability, and expression of the tight junction protein claudin-5 in a rat model of ovarian hyperstimulation syndrome (OHSS). Hyperstimulated rats received excessive doses of pregnant mare serum gonadotropin (PMSG; 50 IU/d) for 4 consecutive days, from d 25 to 28 of life, followed by 25 IU human chorionic gonadotropin (hCG) on d 29. Control rats received 10 IUPMSG on d 27 of life, followed by 10 IU hCG on d 29. GnRHa (leuprolide 100 mu g/kg.d) was administered to some hyperstimulated rats either on d 29 and 30 (short-term GnRHa treatment) or from d 25 to 30 (long-term GnRHa treatment). Ovarian vascular density (vessels per 10 mm(2)) and vessel endothelial area (percent) were assessed by immunohistochemical analysis of the distribution of von Willebrand factor, whereas vascular permeability was evaluated based on leakage of Evans blue. High doses of PMSG and hCG significantly increased ovarian weight, vascular permeability, vascular density, and the vessel endothelial area and significantly reduced expression of claudin-5 protein and mRNA. All of these effects were significantly and dose-dependently inhibited by administration of GnRHa. This suggests that reduced expression of claudin-5 plays a crucial role in the increased ovarian vascular permeability seen in OHSS and that its expression can be modulated by GnRHa treatment. Indeed, preventing redistribution of tight junction proteins in endothelial cells and the resultant loss of endothelial barrier architecture might be the key to protecting patients against massive extravascular fluid accumulation in cases of OHSS.