Theranostics 2022; 12(2):782-795. doi:10.7150/thno.67167 This issue

Research Paper

Resveratrol ameliorates polycystic ovary syndrome via transzonal projections within oocyte-granulosa cell communication

Mingyue Chen1*, Chengyong He1*, Kongyang Zhu1, Zihan Chen1, Zixiao Meng1, Xiaoming Jiang2, Jiali Cai2, Chunyan Yang1, Zhenghong Zuo1✉

1. State Key Laboratory of Cellular Stress Biology, United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Life Sciences, Xiamen University, Xiamen, People's Republic of China.
2. Reproductive Medicine Hospital, Xiamen University Affiliated Chenggong Hospital.
*Co-first authors.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Chen M, He C, Zhu K, Chen Z, Meng Z, Jiang X, Cai J, Yang C, Zuo Z. Resveratrol ameliorates polycystic ovary syndrome via transzonal projections within oocyte-granulosa cell communication. Theranostics 2022; 12(2):782-795. doi:10.7150/thno.67167. Available from https://www.thno.org/v12p0782.htm

File import instruction

Abstract

Graphic abstract

Rationale: Polycystic ovary syndrome (PCOS) is closely linked to follicular dysplasia and impaired bidirectional oocyte-granulosa cell (GC) communication. Given that PCOS is a heterogeneous, multifactorial endocrine disorder, it is important to clarify the pathophysiology of this ovarian disease and identify a specific treatment.

Methods: We generated PCOS rat models based on neonatal tributyltin (TBT) exposure and studied the therapeutic effect and mechanism of resveratrol (RSV), a natural plant polyphenol. Transcriptome analysis was conducted to screen the significantly changed pathways, and a series of experiments, such as quantitative real-time polymerase chain reaction (PCR), Western blot and phalloidin staining, were performed in rat ovaries. We also observed similar changes in human PCOS samples using Gene Expression Omnibus (GEO) database analysis and quantitative real-time PCR.

Results: We first found that injury to transzonal projections (TZPs), which are specialized filopodia that mediate oocyte-GC communication in follicles, may play an important role in the etiology of PCOS. We successfully established PCOS rat models using TBT and found that overexpressed calcium-/calmodulin-dependent protein kinase II beta (CaMKIIβ) inhibited TZP assembly. In addition, TZP disruption and CAMK2B upregulation were also observed in samples from PCOS patients. Moreover, we demonstrated that RSV potently ameliorated ovarian failure and estrus cycle disorder through TZP recovery via increased cytoplasmic calcium levels and excessive phosphorylation of CaMKIIβ.

Conclusions: Our data indicated that upregulation of CaMKIIβ may play a critical role in regulating TZP assembly and may be involved in the pathogenesis of PCOS associated with ovarian dysfunction. Investigation of TZPs and RSV as potent CaMKIIβ activators provides new insight and a therapeutic target for PCOS, which is helpful for improving female reproduction.

Keywords: PCOS, oocyte-GC communication, TZP assembly, resveratrol, CaMKIIβ