Induced Endometriosis in the Baboon (Papio anubis) Increases the Expression of the Proangiogenic Factor CYR61 (CCN1) in Eutopic and Ectopic Endometria1
Abstract
The expression of human CYR61 (cysteine-rich, angiogenic inducer, 61; CCN1) mRNA has been previously shown to be deregulated in the endometrium of women with endometriosis. We have chosen the baboon model (Papio anubis) of induced endometriosis to clarify whether CYR61 mRNA upregulation is predisposed to an inappropriately differentiated endometrium or is deregulated as a response to the presence of ectopic lesions. In the baboon, endometrial CYR61 mRNA expression underwent moderate cyclical variation, with a significant 7.3-fold increase detected at Day 2 postmenses when compared to endometrium from the proliferative and secretory phases. The CYR61 transcript was extensively upregulated in the eutopic endometrium from all baboons with induced endometriosis, as early as 1 mo postinoculation of menstrual tissue into the peritoneal cavity. CYR61 mRNA expression then decreased throughout progression of the disease, but remained higher compared to control tissues. Ectopic endometriotic lesions showed a further increase in CYR61 mRNA, with highest expression found in red lesions. Moreover, the expression levels of CYR61 transcripts correlated significantly with those of VEGF. Immunohistochemistry revealed the presence of CYR61 protein in glandular and luminal epithelial cells as well as in blood vessels of eutopic and ectopic endometrium. As in humans, increased levels of CYR61 mRNA correlated with the development of endometriosis in baboons. The increase of CYR61 mRNA in eutopic endometrium of baboons following peritoneal inoculation with menstrual endometrium provides evidence for a feedback mechanism from resulting lesions to induce a shift in gene expression patterns in the eutopic endometrium.
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Using nonhuman primate models, it has been demonstrated that the presence of menstrual fragments in the peritoneal cavity directly influences gene expression pattern of the eutopic endometrium.
“Using nonhuman primate models of endometriosis, it has been demonstrated that it is the presence of the menstrual fragments in the peritoneal cavity that directly influences gene expression pattern of the eutopic endometrium (97,98).”
From Biomarkers in endometriosis: Challenges and opportunities (2017) · cites this paper as [97]
Chronic inflammation induced by the ectopic presence of endometrial fragments (DAMPs) leads to potential epigenetic modification programming within the eutopic endometrium.
“Chronic inflammation induced by the ectopic presence of endometrial fragments (damage-associated molecular patterns [DAMPs]) lead to potential epigenetic modification programming within the eutopic endometrium.”
From Biomarkers in endometriosis: Challenges and opportunities (2017) · cites this paper as [97]
The initial presence of ectopic foci can influence the gene expression pattern of the eutopic endometrium with disease progression.
“Of particular relevance is the significance of the fact that the initial presence of the ectopic foci can influence the gene expression pattern of the eutopic endometrium with disease progression (97).”
From Biomarkers in endometriosis: Challenges and opportunities (2017) · cites this paper as [97]
Endometriosis is a chronic inflammatory disease wherein sterile inflammation induced by the cyclic deposition of menstrual fragments can lead to pathogenic epigenetic changes in the eutopic endometrium.
“This shows that endometriosis is indeed a chronic inflammatory disease wherein the sterile inflammation induced by the cyclic deposition of menstrual fragments can lead to pathogenic epigenetic changes in the eutopic endometrium.”
From Biomarkers in endometriosis: Challenges and opportunities (2017) · cites this paper as [97]
Cyr61 is up-regulated in eutopic endometrium in women with endometriosis and also in ectopic lesions as well as in experimental endometriosis.
“A highly estrogen-dependent gene, Cyr61, is up-regulated in eutopic endometrium in women with endometriosis and also in ectopic lesions as well as in experimental endometriosis [42, 43].”
From The pathophysiology of endometriosis and adenomyosis, tissue injury and repair (2009) · cites this paper as [43]
In endometriotic lesions, Cyr61 was soon up-regulated.
“In the endometriotic lesions Cyr61, a highly estrogen dependent gene, was soon up-regulated [43].”
From The pathophysiology of endometriosis and adenomyosis, tissue injury and repair (2009) · cites this paper as [43]
Activation of Cyr61 in the eutopic endometrium resulted from activation of the TIAR system with local production of estrogen following tissue injury caused by the biopsy rather than from cross-talk between endometriotic lesions and eutopic endometrium.
“Most probably, the activation of Cyr61 in the eutopic endometrium resulted from the activation of the TIAR system with local production of estrogen following tissue injury that was caused by the biopsy rather than from a ‘cross-talk’ between the endometriotic lesions and the eutopic endometrium as suggested by the authors.”
From The pathophysiology of endometriosis and adenomyosis, tissue injury and repair (2009) · cites this paper as [43]
Cyr61 started to be up-regulated also in the eutopic endometrium of these primarily healthy animals.
“Surprisingly, Cyr61 started to be up-regulated also in the eutopic endometrium of these primarily healthy animals.”
From The pathophysiology of endometriosis and adenomyosis, tissue injury and repair (2009) · cites this paper as [43]
In the baboon model, experimental endometriosis was induced by inoculation of endometrial fragments obtained by endometrial biopsies during the menstrual phase.
“In the baboon model experimental endometriosis was induced by inoculation of endometrial fragments that were obtained by endometrial biopsies during the menstrual phase of the animals.”
From The pathophysiology of endometriosis and adenomyosis, tissue injury and repair (2009) · cites this paper as [43]
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References 38 · Cited by 81
- Authors
- Gashaw, I., Hastings, J. M., Jackson, K. S., Winterhager, E., & Fazleabas, A. T.
- Affiliations
- University of Duisburg-Essen (DE)
- University of Illinois Chicago (US)
- Corresponding author
- Gashaw, Isabella
- Venue
- Biology of Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-06-01
- Volume
- 74
- Issue
- 6
- Pages
- 1060-1066
- ISSN
- 0006-3363 (ISSN-L)
- 1529-7268
- OpenAlex
- W2157560598
- Cited by
- 81
- References
- 38
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 4 · 2013: 5 · 2012: 1
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biology of Reproduction (publishedVersion)
- PubMed (publishedVersion)
- BioOne Complete (BioOne) (submittedVersion)
- Funders
- University of Illinois at Chicago
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD040093, U54-HD40093)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ectopic Pregnancy Diagnosis and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Keywords
- endometriosis, CYR61, baboon model, eutopic endometrium, angiogenesis, vascular endothelial growth factor, gene expression, endometrial differentiation, red lesions
- MeSH terms
- Animals, Choristoma, Endometriosis, Endometrium, Female, Gene Expression Regulation, Immunohistochemistry, RNA, Messenger, Transcription, Genetic, Immediate-Early Proteins, Intercellular Signaling Peptides and Proteins, Vascular Endothelial Growth Factor A, Papio anubis
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