Analyze Diet
Scientific reports2025; 15(1); 3173; doi: 10.1038/s41598-025-86742-0

The myometrial transcriptome changes in mares with endometrosis.

Abstract: Mares with endometrosis exhibit histological changes not only in the endometrium but also in the myometrium that suggest possible functional impairment. The molecular background of these changes is not well understood. We hypothesize that the transcriptomic profile of the mare myometrium varies depending on the degree of endometrosis in mares. Myometria were collected from mares in the mid-luteal phase of the estrous cycle with endometrium categories I, IIA, IIB, and III (∑n = 23), according to Kenney and Doig´s histopathological classification. Myometrial RNA was isolated and subjected to RNA-seq analysis to identify differentially expressed transcriptionally active regions (deTARs) and their contribution to signaling pathways (KEGG database) and biological processes (GO terms). In results, 665, 491 and 499 deTARs were found in the myometrium of mares with endometrium IIA vs I, IIB vs I and III vs I, respectively. 200 common deTARs in the myometrium across all stages of endometrosis (IIA, IIB, and III) vs I were identified. Evaluated deTARs enriched several KEGG pathways including calcium signaling, cAMP signaling, oxytocin signaling, ECM-receptor interaction, and focal adhesion, and were classified into various GO terms including adaptive immune response, tissue homeostasis, muscle contractions, muscle development, and other. In conclusion, transcriptomic alterations in the myometrium of mares with endometrosis may indicate an impaired function of the contractile machinery, mechanisms regulating calcium influx and handling, as well as changes in ECM composition, leading to a decreased contractile activity and structural changes in the myometrium of affected mares.
Publication Date: 2025-01-25 PubMed ID: 39863666PubMed Central: PMC11762791DOI: 10.1038/s41598-025-86742-0Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research aims to understand the changes in the myometrial transcriptome in mares with endometrosis, a uterine disease, by conducting histopathological classifications, RNA-seq analysis, and enrichment of KEGG pathways and GO terms.

Objective of the research

  • The goal of this research was to determine how varying degrees of endometrosis, a uterine disease in mares, affect the transcriptome profile of the myometrium. Test samples were obtained from the myometria of mares in their estrous cycle’s mid-luteal phase.

Research Methodology

  • The test samples included mares with different categories of endometrium. The histopathological classification from Kenney and Doig was used to define these categories as I, IIA, IIB, and III.
  • The RNA in the myometrium was isolated and examined using RNA-seq analysis. This enabled the researchers to identify differentially expressed transcriptionally active regions (deTARs).
  • The researchers then looked at the impact of these deTARs on signaling pathways from the KEGG database, and in the context of the GO terms that represent biological processes.

Key Findings

  • The study found different numbers of deTARs in comparison pairs of myometrium categories, with 665 in IIA vs I, 491 in IIB vs I, and 499 in III vs I.
  • The researchers identified 200 common deTARs in the myometrium across all stages of endometrosis (IIA, IIB, and III) in comparison with stage I.
  • The deTARs enriched several KEGG pathways (calcium signaling, cAMP signaling, oxytocin signaling, ECM-receptor interaction, and focal adhesion) and were categorized into various GO terms (adaptive immune response, tissue homeostasis, muscle contractions, muscle development, and more).

Conclusions

  • The study concluded that there are transcriptomic alterations in the myometrium of mares with endometrosis. These changes could suggest impaired function of the contractile machinery, issues with regulation of calcium influx and handling, and changes in ECM composition.
  • These alterations can lead to decreased contractile activity and structural changes within the myometrium of affected mares, potentially providing insights into the functional changes observed in endometrosis.

Cite This Article

APA
Drzewiecka EM, Molcan T, Sadowska A, Piotrowska-Tomala K, Słyszewska M, Dias GF, Skarżyński DJ, Szóstek-Mioduchowska A. (2025). The myometrial transcriptome changes in mares with endometrosis. Sci Rep, 15(1), 3173. https://doi.org/10.1038/s41598-025-86742-0

Publication

ISSN: 2045-2322
NlmUniqueID: 101563288
Country: England
Language: English
Volume: 15
Issue: 1
Pages: 3173
PII: 3173

Researcher Affiliations

Drzewiecka, Ewa Monika
  • Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748, Olsztyn, Poland. e.drzewiecka@pan.olsztyn.pl.
Molcan, Tomasz
  • Molecular Biology Laboratory, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748, Olsztyn, Poland.
Sadowska, Agnieszka
  • Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748, Olsztyn, Poland.
Piotrowska-Tomala, Katarzyna
  • Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748, Olsztyn, Poland.
Słyszewska, Magda
  • Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748, Olsztyn, Poland.
Dias, Graça Ferreira
  • Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, 1300-477, Lisbon, Portugal.
  • Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 1300-477, Lisbon, Portugal.
Skarżyński, Dariusz Jan
  • Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748, Olsztyn, Poland.
Szóstek-Mioduchowska, Anna
  • Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748, Olsztyn, Poland.

MeSH Terms

  • Female
  • Animals
  • Horses
  • Myometrium / metabolism
  • Myometrium / pathology
  • Transcriptome
  • Endometriosis / genetics
  • Endometriosis / metabolism
  • Endometriosis / pathology
  • Endometriosis / veterinary
  • Horse Diseases / genetics
  • Horse Diseases / metabolism
  • Gene Expression Profiling
  • Endometrium / metabolism
  • Endometrium / pathology
  • Signal Transduction

Grant Funding

  • 2022/06/X/NZ5/01258 / National Science Centre, Poland.

Conflict of Interest Statement

Declarations. Competing interests: The authors declare no competing interests.

References

This article includes 74 references
  1. Allen, W. R. Proceedings of the John P. Hughes International Workshop on Equine Endometritis. Equine Veterinary Journal25, 184–193. 10.1111/j.2042-3306.1993.tb02940.x (2010).
  2. Kenney RM, Doig PA. Equine endometrial biopsy. In Current Therapy in Theriogenology. 723 (Philadelphia: W.B. Saunders, 1986).
  3. Hoffmann C et al. The equine endometrosis: new insights into the pathogenesis. Anim. Reprod. Sci. 111, 261–278 (2009).
  4. Lehmann J et al. Morpho-functional studies regarding the fertility prognosis of mares suffering from equine endometrosis. Theriogenology 76, 1326–1336 (2011).
  5. Szóstek AZ, Lukasik K, Galvão AM, Ferreira-Dias GM, Skarzynski DJ. Impairment of the interleukin system in equine endometrium during the course of endometrosis. Biol. Reprod. 89, 79 (2013).
    pubmed: 23946535doi: 10.1095/biolreprod.113.109447google scholar: lookup
  6. Szóstek A Z et al. mRNA transcription of prostaglandin synthases and their products in the equine endometrium in the course of fibrosis. Theriogenology 78, 768–776 (2012).
  7. Szóstek-Mioduchowska A et al. Transcriptomic profiling of mare endometrium at different stages of endometrosis. Sci. Rep. 13, 16263 (2023).
    pmc: PMC10533846pubmed: 37758834doi: 10.1038/s41598-023-43359-5google scholar: lookup
  8. Rigby SL et al. Mares with delayed uterine clearance have an intrinsic defect in myometrial function. Biol. Reprod. 65, 740–747 (2001).
    pubmed: 11514336doi: 10.1095/biolreprod65.3.740google scholar: lookup
  9. Katila T, Ferreira-Dias G. Evolution of the concepts of endometrosis, post breeding endometritis, and susceptibility of mares. Animals (Basel) .
    pmc: PMC8944725pubmed: 35327176doi: 10.3390/ani12060779google scholar: lookup
  10. Troedsson MH, Liu IK, Crabo BG. Sperm transport and survival in the mare. Theriogenology 49, 905–915 (1998).
    pubmed: 10732099doi: 10.1016/s0093-691x(98)00040-5google scholar: lookup
  11. Stout TA. Embryo-maternal communication during the first 4 weeks of equine pregnancy. Theriogenology 86, 349–354 (2016).
  12. Stout TA, Allen WR. Role of prostaglandins in intrauterine migration of the equine conceptus. Reproduction 121, 771–775 (2001).
    pubmed: 11427165
  13. Shynlova O, Nadeem L, Zhang J, Dunk C, Lye S. Reprint of: Myometrial activation: Novel concepts underlying labor. Placenta 98, 29–37 (2020).
  14. Piotrowska-Tomala KK, Jonczyk AW, Skarzynski DJ, Szóstek-Mioduchowska AZ. Luteinizing hormone and ovarian steroids affect in vitro prostaglandin production in the equine myometrium and endometrium. Theriogenology 153, 1–8 (2020).
  15. Hanada M, Maeda Y, Oikawa MA. Histopathological characteristics of endometrosis in thoroughbred mares in Japan: Results from 50 necropsy cases. J. Equine Sci. 25, 45–52 (2014).
    pmc: PMC4090358pubmed: 25013358doi: 10.1294/jes.25.45google scholar: lookup
  16. Troedsson MH. Uterine clearance and resistance to persistent endometritis in the mare. Theriogenology 52, 461–471 (1999).
    pubmed: 10734380doi: 10.1016/s0093-691x(99)00143-0google scholar: lookup
  17. LeBlanc MM et al. Scintigraphic measurement of uterine clearance in normal mares and mares with recurrent endometritis. Equine Vet. J. 26, 109–113 (1994).
  18. LeBlanc MM, Neuwirth L, Jones L, Cage C, Mauragis D. Differences in uterine position of reproductively normal mares and those with delayed uterine clearance detected by scintigraphy. Theriogenology 50, 49–54 (1998).
    pubmed: 10734473doi: 10.1016/s0093-691x(98)00112-5google scholar: lookup
  19. Drobnis EZ, Overstreet JW. Natural history of mammalian spermatozoa in the female reproductive tract. Oxf. Rev. Reprod. Biol. 14, 1–45 (1992).
    pubmed: 1437209
  20. Liepina E, Antane V. Endometrial histological changes and pregnancy rates in mares impaired cervical drainage. (2010).
  21. Piotrowska-Tomala KK et al. The effect of lysophosphatidic acid (LPA) on contractions in equine myometrium during the stages of fibrosis at the early and mid-luteal phase of the Estrous Cycle. J. Equine Vet. Sci. 66, 146 (2018).
  22. Witkowski M et al. Next-generation sequencing analysis discloses genes implicated in equine endometrosis that may lead to tumorigenesis. Theriogenology 189, 158–166 (2022).
  23. Wójtowicz A et al. The potential role of miRNAs and regulation of their expression in the development of mare endometrial fibrosis. Sci. Rep. 13(1), 15938 (2023).
    pmc: PMC10518347pubmed: 37743390doi: 10.1038/s41598-023-42149-3google scholar: lookup
  24. Geeves MA. Review: The ATPase mechanism of myosin and actomyosin. Biopolymers 105, 483–491 (2016).
    pubmed: 27061920doi: 10.1002/bip.22853google scholar: lookup
  25. Gash MC, Kandle PF, Murray IV, Varacallo M. Physiology, Muscle Contraction. StatPearls [Internet] [Updated 2023 Apr 1], Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
    pubmed: 30725825
  26. Carsten ME. Uterine smooth muscle: Troponin. Arch. Biochem. Biophys. 147, 353–357 (1971).
    pubmed: 4255953doi: 10.1016/0003-9861(71)90346-8google scholar: lookup
  27. Barrett KE, Barman SM, Boitano S, Brooks H. Ganong’s Review of Medical Physiology, 24th Edition. (Mcgraw-hill, 2012).
  28. Rehman KS, Yin S, Mayhew BA, Word RA, Rainey WE. Human myometrial adaptation to pregnancy: cDNA microarray gene expression profiling of myometrium from non-pregnant and pregnant women. Mol. Hum. Reprod. 9, 681–700 (2003).
    pubmed: 14561811doi: 10.1093/molehr/gag078google scholar: lookup
  29. Pehlivanoğlu B, Bayrak S, Doğan M. A close look at the contraction and relaxation of the myometrium; the role of calcium. J. Turk. Ger. Gynecol. Assoc. 14, 230–234 (2013).
    pmc: PMC3935537pubmed: 24592112doi: 10.5152/jtgga.2013.67763google scholar: lookup
  30. Zangeneh FZ, Hantoushzadeh S. The physiological basis with uterine myometrium contractions from electro-mechanical/hormonal myofibril function to the term and preterm labor. Heliyon 9, e22259 (2023).
  31. Arimura T et al. Identification, characterization, and functional analysis of heart-specific myosin light chain phosphatase small subunit. J. Biol. Chem. 276, 6073–6082 (2001).
    pubmed: 11067852doi: 10.1074/jbc.m008566200google scholar: lookup
  32. Fujioka M et al. A new isoform of human myosin phosphatase targeting/regulatory subunit (MYPT2): cDNA cloning, tissue expression, and chromosomal mapping. Genomics 49, 59–68 (1998).
    pubmed: 9570949doi: 10.1006/geno.1998.5222google scholar: lookup
  33. Wray S. in Handbook of Cell Signaling (Second Edition). 1009–1025 (Academic Press, 2010).
  34. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: Dynamics, homeostasis and remodelling. Nat. Rev. Mol. Cell. Biol. 4, 517–529 (2003).
    pubmed: 12838335doi: 10.1038/nrm1155google scholar: lookup
  35. Sanborn BM. Relationship of ion channel activity to control of myometrial calcium. J. Soc. Gynecol. Investig. 7, 4–11 (2000).
    pubmed: 10732311doi: 10.1016/s1071-5576(99)00051-9google scholar: lookup
  36. Rhee SG. Regulation of phosphoinositide-specific phospholipase C. Annu. Rev. Biochem. 70, 281–312 (2001).
  37. Mhaouty-Kodja S, Houdeau E, Legrand C. Regulation of myometrial phospholipase C system and uterine contraction by beta-adrenergic receptors in midpregnant rat. Biol. Reprod. 70, 570–576 (2004).
    pubmed: 14585815doi: 10.1095/biolreprod.103.021535google scholar: lookup
  38. Awad SS, Lamb HK, Morgan JM, Dunlop W, Gillespie JI. Differential expression of ryanodine receptor RyR2 mRNA in the non-pregnant and pregnant human myometrium. Biochem. J. 322(Pt 3), 777–783 (1997).
    pmc: PMC1218255pubmed: 9148749doi: 10.1042/bj3220777google scholar: lookup
  39. Martin C et al. Pregnant rat myometrial cells show heterogeneous ryanodine- and caffeine-sensitive calcium stores. Am. J. Physiol. 277, C243-252 (1999).
  40. Young RC, Mathur SP. Focal sarcoplasmic reticulum calcium stores and diffuse inositol 1,4,5-trisphosphate and ryanodine receptors in human myometrium. Cell Calcium 26, 69–75 (1999).
    pubmed: 10892572doi: 10.1054/ceca.1999.0056google scholar: lookup
  41. Qu M et al. Phenanthroline relaxes uterine contractions induced by diverse contractile agents by decreasing cytosolic calcium concentration. Eur. J. Pharmacol. 968, 176343 (2024).
  42. Ousey JC, Freestone N, Fowden AL, Mason WT, Rossdale PD. The effects of oxytocin and progestagens on myometrial contractility in vitro during equine pregnancy. J. Reprod. Fertil. Suppl. 681–691 (2000).
    pubmed: 20681184
  43. Hamshaw I et al. PGF(2α) induces a pro-labour phenotypical switch in human myometrial cells that can be inhibited with PGF(2α) receptor antagonists. Front. Pharmacol. 14, 1285779 (2023).
    pmc: PMC10752971pubmed: 38155905doi: 10.3389/fphar.2023.1285779google scholar: lookup
  44. Kennedy EA, Jurado KA. IL-33 is alarmin the uterus for labor. Immunity 56, 467–469 (2023).
    pubmed: 36921571doi: 10.1016/j.immuni.2023.02.007google scholar: lookup
  45. Di Liberto G et al. A critical role for PKC zeta in endothelin-1-induced uterine contractions at the end of pregnancy. Am. J. Physiol. Cell Physiol. 285, C599-607 (2003).
    pubmed: 12748064doi: 10.1152/ajpcell.00040.2003google scholar: lookup
  46. Chen L et al. Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor. Elife .
    pmc: PMC9398448pubmed: 35998104doi: 10.7554/elife.75072google scholar: lookup
  47. Yallampalli C. Control of Uterine Contractility. 285–309 (Boca Raton, FL: CRC Press, 1994).
  48. Kiani C, Chen L, Wu YJ, Yee AJ, Yang BB. Structure and function of aggrecan. Cell Res. 12, 19–32 (2002).
    pubmed: 11942407doi: 10.1038/sj.cr.7290106google scholar: lookup
  49. Morawski M, Brückner G, Arendt T, Matthews RT. Aggrecan: Beyond cartilage and into the brain. Int. J. Biochem. Cell Biol. 44, 690–693 (2012).
    pubmed: 22297263doi: 10.1016/j.biocel.2012.01.010google scholar: lookup
  50. Du KL et al. Myocardin is a critical serum response factor cofactor in the transcriptional program regulating smooth muscle cell differentiation. Mol. Cell Biol. 23, 2425–2437 (2003).
  51. Kim HR et al. Egr1 is rapidly and transiently induced by estrogen and bisphenol A via activation of nuclear estrogen receptor-dependent ERK1/2 pathway in the uterus. Reprod. Toxicol. 50, 60–67 (2014).
  52. Wu SP et al. Dynamic transcriptome, accessible genome, and PGR cistrome profiles in the human myometrium. FASEB J. 34, 2252–2268 (2020).
    pmc: PMC10189786pubmed: 31908010doi: 10.1096/fj.201902654rgoogle scholar: lookup
  53. Wray S, Prendergast C. The myometrium: From excitation to contractions and labour. Adv. Exp. Med. Biol. 1124, 233–263 (2019).
    pubmed: 31183830doi: 10.1007/978-981-13-5895-1_10google scholar: lookup
  54. Montagnana M et al. Evaluation of metalloproteinases 2 and 9 and their inhibitors in physiologic and pre-eclamptic pregnancy. J. Clin. Lab. Anal. 23, 88–92 (2009).
    pmc: PMC6649012pubmed: 19288452doi: 10.1002/jcla.20295google scholar: lookup
  55. Yin Z, Sada AA, Reslan OM, Narula N, Khalil RA. Increased MMPs expression and decreased contraction in the rat myometrium during pregnancy and in response to prolonged stretch and sex hormones. Am. J. Physiol. Endocrinol. Metab. 303, E55-70 (2012).
    pmc: PMC3404560pubmed: 22496348doi: 10.1152/ajpendo.00553.2011google scholar: lookup
  56. Ginther OJ et al. Comparative study of the dynamics of follicular waves in mares and women. Biol. Reprod. 71, 1195–1201 (2004).
  57. McKinnon AO, Squires EL, Vaala WE, Varner DD. Equine Reproduction, second ed.. The Veterinary Journal (2011).
  58. Ricketts SW. The technique and clinical application of endometrial biopsy in the mare. Equine Vet. J. 7(2), 102–108 (1975).
  59. Ricketts SW, Alonso S. Assessment of the breeding prognosis of mares using paired endometrial biopsy techniques. Equine Vet. J. 23(3), 185–188 (1991).
  60. Nielsen JM. Endometritis in the mare: A diagnostic study comparing cultures from swab and biopsy. Theriogenology 64(3), 510–518 (2005).
  61. Bolger AM, Lohse M, Usadel B. Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).
  62. Dobin A et al. STAR: Ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
  63. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
    pmc: PMC4302049pubmed: 25516281doi: 10.1186/s13059-014-0550-8google scholar: lookup
  64. Ignatiadis N, Klaus B, Zaugg JB, Huber W. Data-driven hypothesis weighting increases detection power in genome-scale multiple testing. Nat. Methods 13, 577–580 (2016).
    pmc: PMC4930141pubmed: 27240256doi: 10.1038/nmeth.3885google scholar: lookup
  65. Stephens M. False discovery rates: A new deal. Biostatistics 18, 275–294 (2017).
  66. Durinck S, Spellman PT, Birney E, Huber W. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat. Protoc. 4, 1184–1191 (2009).
    pmc: PMC3159387pubmed: 19617889doi: 10.1038/nprot.2009.97google scholar: lookup
  67. Yu G, Wang LG, Han Y, He QY. clusterProfiler: An R package for comparing biological themes among gene clusters. Omics 16, 284–287 (2012).
    pmc: PMC3339379pubmed: 22455463doi: 10.1089/omi.2011.0118google scholar: lookup
  68. Yu G, Wang LG, Yan GR, He QY. DOSE: An R/Bioconductor package for disease ontology semantic and enrichment analysis. Bioinformatics 31, 608–609 (2015).
    pubmed: 25677125doi: 10.1093/bioinformatics/btu684google scholar: lookup
  69. Carlson M. org.Hs.eg.db: Genome wide annotation for Human. R package version 3.8.2.. (2017).
  70. Kanehisa M. Toward understanding the origin and evolution of cellular organisms. Protein Sci. 28, 1947–1951 (2019).
    pmc: PMC6798127pubmed: 31441146doi: 10.1002/pro.3715google scholar: lookup
  71. Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 51, D587–D592 (2023).
    pmc: PMC9825424pubmed: 36300620doi: 10.1093/nar/gkac963google scholar: lookup
  72. Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000).
    pmc: PMC102409pubmed: 10592173doi: 10.1093/nar/28.1.27google scholar: lookup
  73. Andersen CL, Jensen JL, Ørntoft TF. Normalization of real-time quantitative reverse transcription-PCR data: A model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 64, 5245–5250 (2004).
    pubmed: 15289330doi: 10.1158/0008-5472.can-04-0496google scholar: lookup
  74. Zhao S, Fernald RD. Comprehensive algorithm for quantitative real-time polymerase chain reaction. J. Comput. Biol. 12, 1047–1064 (2005).
    pmc: PMC2716216pubmed: 16241897doi: 10.1089/cmb.2005.12.1047google scholar: lookup

Citations

This article has been cited 0 times.