Tie1 contributes to the development of ovarian hyperstimulation syndrome under the regulation of EGR1 in granulosa cells

Abstract

The expression of tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 (Tie1), a transmembrane protein expressed almost exclusively by endothelial cells, has been reported in granulosa cells. However, its significance in ovarian hyperstimulation syndrome (OHSS), which can occur after the injection of gonadotropins in infertile women undergoing controlled ovarian stimulation, is unknown. Here, we report significantly increased Tie1 and vascular endothelial growth factor (VEGF) expression in cultured granulosa cells from OHSS patients, as well as ovaries from rats with experimentally established OHSS, compared to controls, with the levels of both proteins also increasing in granulosa and SVOG cells (a nontumorigenic human granulosa-lutein cell line) treated with an acute dose of human chorionic gonadotropin (hCG). Tie1 silencing abolished the hCG-induced VEGF level in SVOG cells and attenuated the progression of OHSS in rats, as determined by histological analysis. Further studies in SVOG cells revealed that the hCG-induced upregulation of Tie1 expression involved the phosphoinositide 3-kinase/protein kinase B signaling pathway. We also report that early growth response protein 1 (EGR1), whose expression was also upregulated by hCG, bound directly to the Tie1 promoter and activated its transcription. Taken together, our results indicate that Tie1 may be a therapeutic target in cases of moderate-to-severe OHSS. Further studies are needed to address its clinical relevance.

Infertility: Ovarian hyperstimulation syndrome

Identification of a hormone-sensitive signaling pathway in a subset of ovarian cells could lead to better treatment for women experiencing adverse events associated with infertility treatment. Up to 8% of women who receive the ‘pregnancy hormone’ human chorionic gonadotropin (hCG) during fertility care will develop ovarian hyperstimulation syndrome (OHSS), a condition that can be debilitating or even fatal. Researchers led by Qinju Chen of Shanghai JiaoTong University and Shaorong Gao of Tongji University, Shanghai, China, have identified links between blood vessel function and risk of hCG-associated complications. Working with both human cells and animal models, they showed a strong connection between hCG exposure and expression of a signaling protein associated with blood vessels in certain ovarian cells. Targeted inactivation of this protein prevented OHSS in rats, suggesting it could offer a drug target for at-risk women.