Research Paper
Adipocyte-derived exosomal miR-30c-5p promotes ovarian angiogenesis in polycystic ovary syndrome via the SOCS3/STAT3/VEGFA pathway
- 1 Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan 430060, China
- 2 Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan 430060, China
- 3 Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China
Received: August 17, 2022 Accepted: November 16, 2022
https://doi.org/10.18632/aging.How to Cite
Copyright: © 2022 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Polycystic ovary syndrome (PCOS) is a systemic endocrine disease affecting the reproductive health of women. Ovarian angiogenesis in PCOS patients exhibits abnormal, manifested as increased ovarian stromal vascularization and upregulated proangiogenic factors such as vascular endothelial growth factor (VEGF). However, the specific mechanisms underlying these changes in PCOS remain unknown. In this study, we induced the adipogenic differentiation of preadipocyte 3T3-L1 cells and found that adipocyte-derived exosomes promoted proliferation, migration, tube formation and VEGFA expression in human ovarian microvascular endothelial cells (HOMECs) by delivering miR-30c-5p. Mechanistically, dual luciferase reporter assay demonstrated that miR-30c-5p directly targeted the 3’- untranslated region (UTR) of suppressor of cytokine signaling 3 (SOCS3) mRNA. In addition, adipocyte-derived exosomal miR-30c-5p activated signal transducer and activator of transcription 3 (STAT3)/VEGFA pathway in HOMECs via targeting SOCS3. In vivo experiments indicated that tail vein injection of adipocyte-derived exosomes exacerbated endocrine and metabolic disorders and ovarian angiogenesis in mice with PCOS via delivery of miR-30c-5p. Taken together, the study revealed that adipocyte-derived exosomal miR-30c-5p promotes ovarian angiogenesis via the SOCS3/STAT3/VEGFA pathway, thereby participating in the pathogenesis of PCOS.
Abbreviations
AFs: antral follicles; AT: adipose tissue; ATCC: American type culture collection; CCK-8: cell counting kit-8; CFs: cystic follicles; CL: corpus luteum; DAPI: 4’:6-diamidino-2-phenylindole; DHEA: dehydroepiandrosterone; DMEM: Dulbecco’s modified eagle’s medium; ECs: endothelial cells; EVs: extracellular vesicles; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; FSH: follicle-stimulating hormone; GCs: granulosa cells; HE: hematoxylin and eosin; HOMA-IR: homeostasis model assessment of insulin resistance; HOMECs: human ovarian microvascular endothelial cells; HRP: horseradish peroxidase; HUVECs: human umbilical vein endothelial cells; IF: immunofluorescence; IHC: immunohistochemical; IL-6: interleukin-6; JAK: Janus kinase; miRNAs: microRNAs; ncRNAs: noncoding RNAs; NTA: nanoparticle tracking analysis; PBS: phosphate-buffered saline; PCNA: proliferating cell nuclear antigen; PCOS: polycystic ovary syndrome; PFs: primary follicles; PVDF: polyvinylidene fluoride; RIPA: radio immunoprecipitation assay; SD: standard deviation; SDS-PAGE: sodium dodecyl sulfate–polyacrylamide gel electrophoresis; SFs: secondary follicles; SNHG9: small nucleolar RNA host gene 9; SOCS3: suppressor of cytokine signaling 3; STAT3: signal transducer and activator of transcription 3; T: testosterone; TEM: transmission electron microscopy; TRADD: TNF receptor-associated death domain; UTR: untranslated region; VEGF: vascular endothelial growth factor; VEGFA: vascular endothelial growth factor A.