Changes in Inflammatory Cytokines, Vascular Markers, Cell Cycle Regulators, and Gonadotropin Receptors in Granulosa Cells of COVID-19 Infected Women
Gene Expression Analysis in Granulosa Cells of COVID-19 Infected Women
DOI:
https://doi.org/10.31661/gmj.v13i.3625Keywords:
SARS-CoV-2; COVID-19; Inflammatory Gene; Cell CycleAbstract
Background: COVID-19 infection can negatively affect multiple organ systems, including the reproductive system. Previous research has indicated altered levels of inflammatory markers in the reproductive tissues of women with chronic diseases. This study aimed to assess the expression of inflammatory, vascular, cell cycle, and gonadotropin receptor genes in the granulosa cells and oocytes of women with recent COVID-19 infection undergoing Assisted Reproductive Technology (ART), compared to healthy controls. Materials and Methods: The study involved 15 women who had tested positive for COVID-19 within three months of ART treatment and 15 age-matched healthy women as controls. Granulosa cells were collected during oocyte retrieval, and RNA was isolated to analyze gene expression using quantitative real-time PCR. The evaluated genes included inflammatory cytokines (IL-1B, TNF-α, IL-6, IL-8), vascular genes (VEGF, ANGPT1), cell cycle regulators (FOXL2, Cyclin D1, Cyclin D2, KLF4), and gonadotropin receptors (LHCGR, FSHR). Results: Results showed significantly higher expression of inflammatory cytokines in the granulosa cells of COVID-19 positive women, including IL-1B (4.2-fold), TNF-α (3.8-fold), IL-8 (2.5-fold), and IL-6 (3.2-fold). Vascular genes VEGF and ANGPT1 were also overexpressed, while FOXL2 was downregulated and Cyclin D1/D2 were upregulated in the study group. However, LH and FSH receptor expression remained similar between both groups. Conclusion: The present study demonstrates altered gene expression of inflammatory cytokines, vascular factors and cell cycle regulators in granulosa cells and oocytes of COVID-19 positive women undergoing ART. The dysregulated molecular pathways could potentially impair folliculogenesis and oocyte development in SARS-CoV-2 infected individuals.
References
Phelan N, Behan LA, Owens L. The impact of the COVID-19 pandemic on women's reproductive health. Front Endocrinol. 2021;12:642755.
https://doi.org/10.3389/fendo.2021.642755
Jamali E, Shapoori S, Farrokhi MR, Vakili S, Rostamzadeh D, Iravanpour F et al. Effect of Disease-Modifying Therapies on COVID-19 Vaccination Efficacy in Multiple Sclerosis Patients: A Comprehensive Review. Viral Immunol. 2023;36(6):368-77.
https://doi.org/10.1089/vim.2023.0035
Vakili S, Roshanisefat S, Ghahramani L, Jamalnia S. A Report of an Iranian COVID-19 Case in a Laparoscopic Cholecystectomy Patient: A Case Report and Insights. Journal of Health Sciences & Surveillance System. 2021;9(2):135-9.
https://doi.org/10.21203/rs.3.rs-25302/v1
Vakili S, Akbari H, Jamalnia S. Clinical and Laboratory findings on the differences between h1n1 influenza and coronavirus disease-2019 (covid-19): focusing on the treatment approach. Clin Pulm Med. 2020;27(4):87-93.
https://doi.org/10.1097/CPM.0000000000000362
Wu M, Ma L, Xue L, Zhu Q, Zhou S, Dai J et al. Co-expression of the SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in human ovaries: identification of cell types and trends with age. Genomics. 2021;113(6):3449-60.
https://doi.org/10.1016/j.ygeno.2021.08.012
Li M-Y, Li L, Zhang Y, Wang X-S. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty. 2020;9(02):23-9.
https://doi.org/10.1186/s40249-020-00662-x
Goad J, Rudolph J, Rajkovic A. Female reproductive tract has low concentration of SARS-CoV2 receptors. Plos one. 2020;15(12):e0243959.
https://doi.org/10.1371/journal.pone.0243959
D'Ippolito S, Turchiano F, Vitagliano A, Scutiero G, Lanzone A, Scambia G, Greco P. Is there a role for SARS-CoV-2/COVID-19 on the female reproductive system? Front physiol. 2022;13:845156.
https://doi.org/10.3389/fphys.2022.845156
Vakili S, Savardashtaki A, Parsanezhad ME, Mosallanezhad Z, Foruhari S, Sabetian S et al. SARS-CoV-2 RNA in Follicular Fluid, Granulosa Cells, and Oocytes of COVID-19 Infected Women Applying for Assisted Reproductive Technology. Galen Med J. 2022;11:e2638-e.
https://doi.org/10.31661/gmj.v11i.2638
Hu X, Feng G, Chen Q, Sang Y, Chen Q, Wang S et al. The impact and inflammatory characteristics of SARS-CoV-2 infection during ovarian stimulation on the outcomes of assisted reproductive treatment. Front Endocrinol. 2024;15:1353068.
https://doi.org/10.3389/fendo.2024.1353068
Wu L, Liu D, Fang X, Zhang Y, Guo N, Lu F et al. Increased serum IL-12 levels are associated with adverse IVF outcomes. J Reprod Immunol. 2023;159:103990.
https://doi.org/10.1016/j.jri.2023.103990
Sabetian S, Namavar Jahromi B, Feiz F, Castiglioni I, Cava C, Vakili S. Clinical Guidelines on the Use of Assisted Reproductive Technology During Covid-19 Pandemic: A Minireview of the Current Literature. Journal of Health Sciences & Surveillance System. 2022;10(1):13-8.
https://doi.org/10.3390/cells10061480
Carp-Veliscu A, Mehedintu C, Frincu F, Bratila E, Rasu S, Iordache I et al. The effects of SARS-CoV-2 infection on female fertility: a review of the literature. Int J Environ Res Public Health. 2022;19(2):984.
https://doi.org/10.3390/ijerph19020984
Săndulescu MS, Văduva C-C, Siminel MA, Dijmărescu AL, Vrabie SC, Camen IV et al. Impact of COVID-19 on fertility and assisted reproductive technology (ART): A systematic review. Rom J Morphol Embryol. 2022;63(3):503.
https://doi.org/10.47162/RJME.63.3.04
Rimon-Dahari N, Yerushalmi-Heinemann L, Alyagor L, Dekel N. Ovarian folliculogenesis. Molecular mechanisms of cell differentiation in gonad development. 2016:167-90.
https://doi.org/10.1007/978-3-319-31973-5_7
Alam MH, Miyano T. Interaction between growing oocytes and granulosa cells in vitro. Reproductive medicine and biology. 2020;19(1):13-23.
https://doi.org/10.1002/rmb2.12292
Ruebel ML, Cotter M, Sims CR, Moutos DM, Badger TM, Cleves MA et al. Obesity modulates inflammation and lipid metabolism oocyte gene expression: a single-cell transcriptome perspective. J Clin Endocrinol Metab. 2017;102(6):2029-38.
https://doi.org/10.1210/jc.2016-3524
Lee C, Choi WJ. Overview of COVID-19 inflammatory pathogenesis from the therapeutic perspective. Arch Pharm Res. 2021;44(1):99-116.
https://doi.org/10.1007/s12272-020-01301-7
Darif D, Hammi I, Kihel A, Saik IEI, Guessous F, Akarid K. The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong? Microb Pathog. 2021;153:104799.
https://doi.org/10.1016/j.micpath.2021.104799
Silva JR, Lima FE, Souza AL, Silva AW. Interleukin-1β and TNF-α systems in ovarian follicles and their roles during follicular development, oocyte maturation and ovulation. Zygote. 2020;28(4):270-7.
https://doi.org/10.1017/S0967199420000222
Guzmán A, Hernández-Coronado CG, Gutiérrez CG, Rosales-Torres AM. The vascular endothelial growth factor (VEGF) system as a key regulator of ovarian follicle angiogenesis and growth. Mol Reprod Dev. 2023;90(4):201-17.
https://doi.org/10.1002/mrd.23683
Da Broi M, Giorgi V, Wang F, Keefe D, Albertini D, Navarro P. Influence of follicular fluid and cumulus cells on oocyte quality: clinical implications. Journal of assisted reproduction and genetics. 2018;35:735-51.
https://doi.org/10.1007/s10815-018-1143-3
Chen H-T, Wu W-B, Lin J-J, Lai T-H. Identification of potential angiogenic biomarkers in human follicular fluid for predicting oocyte maturity. Front Endocrinol. 2023;14:1173079.
https://doi.org/10.3389/fendo.2023.1173079
Ito H, Emori C, Kobayashi M, Maruyama N, Fujii W, Naito K, Sugiura K. Cooperative effects of oocytes and estrogen on the forkhead box L2 expression in mural granulosa cells in mice. Sci Rep. 2022;12(1):20158.
https://doi.org/10.1038/s41598-022-24680-x
Georges A, Auguste A, Bessiere L, Vanet A, Todeschini A-L, Veitia RA. FOXL2: a central transcription factor of the ovary. J mol endocrinol. 2014;52(1):R17-R33.
Published
Issue
Section
License
Copyright (c) 2024 Galen Medical Journal
This work is licensed under a Creative Commons Attribution 4.0 International License.
