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

Lihua Sun,Qiuju Chen,Rongxiang Wang,Shaorong Gao,Hui Tian,Songguo Xue,Caixia Zhang,Xue Xue,Hongjuan Ye,Yu Liu

doi:10.1038/s12276-021-00722-8

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.

Highlights

In the first week of pregnancy, cells surrounding the newly fertilized egg produce human chorionic gonadotropin, the so-called “pregnancy hormone”, which subsequently stimulates the production of progesterone to maintain pregnancy and establish the placenta
vascular endothelial growth factor (VEGF) and Tie[1] levels increase significantly in granulosa cells from ovarian hyperstimulation syndrome (OHSS) patients To examine the involvement of vascular tissue-specific signaling pathways in the pathophysiology of OHSS, in which the integrity of ovarian blood vessels is compromised by human chorionic gonadotropin (hCG), thereby resulting in fluid leakage and accumulation in the abdomen and sometimes the chest[2,4], we focused our attention on one key protein from the VEGF signaling pathway (i.e., VEGF) and one from the Ang-Tie signaling pathway (i.e., Tie1)
VEGF mRNA and protein levels were significantly higher in granulosa cells from OHSS patients than in cells from controls (Fig. 1b, c), and VEGF levels were increased twofold in granulosa cells from controls cultured in the presence of hCG for 24 h compared to untreated cells (Fig. 1d, e)

Summary

Introduction

In the first week of pregnancy, cells surrounding the newly fertilized egg produce human chorionic gonadotropin (hCG), the so-called “pregnancy hormone”, which subsequently stimulates the production of progesterone to maintain pregnancy and establish the placenta. In infertile women undergoing controlled ovarian stimulation, hCG is administered at extremely high doses to stimulate the release of eggs from mature follicles[1]. These women are at an increased risk of developing ovarian hyperstimulation syndrome (OHSS), with approximately 3–8% of women experiencing moderate-to-severe symptoms within weeks of hCG injection[2,3]. The risk of developing OHSS is further increased in women receiving multiple hCG injections or in those achieving pregnancy. Several cases of spontaneous OHSS have been reported, and these women have a mutation in the follicle-stimulating hormone receptor (FSHR) gene, which displays an increased sensitivity to hCG6,7

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