TGF-β1 induces VEGF expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome

Lanlan Fang, Yiran Li, Sijia Wang, Yuxi Li, Hsun‐Ming Chang, Yuyin Yi, Yang Yan, Avinash Thakur, Peter C. K. Leung, Jung‐Chien Cheng, Yingpu Sun
In: Experimental & Molecular Medicine · 2020 · vol. 52(3) , pp. 450–460 · doi:10.1038/s12276-020-0396-y · PMID:32152452 · W3009484862
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Abstract

Ovarian hyperstimulation syndrome (OHSS) is one of the most serious and iatrogenic complications that can occur during in vitro fertilization treatment. Although the pathogenesis of OHSS is not fully understood, vascular endothelial growth factor (VEGF) has been recognized as an important mediator of the development of OHSS. Transforming growth factor-beta-1 (TGF-β1) is known to regulate various ovarian functions. However, whether VEGF can be regulated by TGF-β1 in human granulosa cells has not been determined. In addition, the role of TGF-β1 in the pathogenesis of OHSS remains unknown. In the present study, we demonstrate that TGF-β1 stimulates VEGF expression in and secretion from both immortalized human granulosa-lutein (hGL) cells and primary hGL cells. Our results demonstrate that the SMAD2/3, ERK1/2, and p38 MAPK signaling pathways are involved in TGF-β1-induced VEGF expression and secretion. Using a mouse OHSS model, we show that the expression levels of TGF-β1 and VEGF are increased in the ovaries of OHSS mice. Blocking TGF-β1 signaling inhibits the development of OHSS by attenuating VEGF expression. Moreover, clinical results reveal that the protein levels of TGF-β1 and VEGF are increased in the follicular fluid of patients with OHSS, and that the levels of these two proteins in the follicular fluid are positively correlated. The results of this study help to elucidate the mechanisms by which VEGF expression is regulated in hGL cells, which could lead to the development of alternative therapeutic approaches for treating OHSS.

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