Ovarian hyperstimulation syndrome inhibition by targeting VEGF, COX-2 and Calcium pathways: a preclinical randomized study

Abstract

Objective: The efficacy of vascular endothelial growth factor (VEGF), COX-2, calcium and aromatase inhibitors in an ovarian hyperstimulation syndrome (OHSS) rat model was tested.

Methods: One hundred and eight female Wistar rats were randomly divided in nine groups. The control group received saline, while the OHSS group received rec-FSH for 4 consecutive days. The other seven groups received rec-FSH (4d) and Bevacizumab twice, Parecoxib daily, Verapamil daily, Parecoxib daily and Bevacizumab twice, Verapamil daily and Bevacizumab twice, Parecoxib and Verapamil daily, Letrozole and Meloxicam daily, respectively. All groups received also hCG at the 5th day.

Results: All intervention groups were characterized by reduced vascular permeability compared to the OHSS group, which in the groups of Verapamil (Calcium inhibition) and Parecoxib + Verapamil (COX-2 + Calcium inhibition) presented significant statistical difference. The Verapamil group showed the lowest corpus luteum formation, while the Parecoxib (COX-2 inhibition), the Parecoxib + Verapamil (COX-2 + Calcium inhibition), the Bevacizumab + Parecoxib (VEGF + COX-2 inhibition) and the Bevacizumab + Verapamil (VEGF + Calcium inhibition) groups were also characterized by lower corpus luteum numbers compared to the OHSS group. Furthermore, lower graafian follicle formation was observed in the above groups, while the ovarian weight and the hormonal profile were not significantly affected.

Conclusions: Studying the different check points of the VEGF pathway, we conclude that targeting calcium pathways could be beneficial for the vascular permeability control in an OHSS animal model.

Chinese abstract

目的：检测血管内皮生长因子（VEGF）、COX-2、钙和芳香化酶抑制剂对卵巢过度刺激综合征（OHSS）大鼠模型的效果。

方法：108只雌性Wistar大鼠随机分成9组。对照组用生理盐水处理、而卵巢过度刺激综合征组用重组-FSH连续用药4天。另外7组分别用4天重组-FSH和两次贝伐单抗；每日帕瑞昔布钠；每日维拉帕米；每日帕瑞昔布钠和两次维拉帕米；每日维拉帕米和两次贝伐单抗；每日帕瑞昔布钠和维拉帕米；每日来曲唑和美洛昔康处理。全部9组在第5天用人绒毛膜促性腺激素处理。

结果：对比卵巢过度刺激综合征组，所有干预组均有血管通透性降低的特征，其中维拉帕米组（钙离子拮抗制）和帕瑞昔布钠+维拉帕米组（COX-2+钙离子拮抗剂）有显著的统计学差异。相比OHSS组，维拉帕米组黄体形成数最少，而帕瑞昔布钠组（COX-2拮抗剂）、帕瑞昔布钠+维拉帕米组（COX-2+钙离子拮抗剂）、帕瑞昔布钠+贝伐单抗组（VEGF+COX-2拮抗剂）和贝伐单抗+维拉帕米（VEGF+钙离子拮抗剂）组也有较少黄体数。此外，以上各组中，形成成熟卵泡的数目也较少，而卵巢重量和激素受到的影响并不明显。

结论：通过研究不同的VEGF通路的检测点，我们得出以下结论：在卵巢过度刺激综合征的动物模型中，钙信号通路可能对控制血管通透性有益。

• Calcium inhibition
• Cox-2 inhibition
• ovarian hyperstimulation
• VEGF inhibition