Hypoxia: The force of endometriosis

Abstract

Aim: Summarize recent findings of how hypoxia regulates numerous important processes to facilitate the implantation, proliferation and progression of ectopic endometriotic lesions. Methods: Most up-to-date evidences about how hypoxia contributes to the disease pathogenesis of endometriosis and potential therapeutic approaches were collected by conducting a comprehensive search of medical literature electronic databases. Quality of data was analyzed by experienced experts including gynecologist and basic scientists. Results: Uterus is a highly vascularized organ, which makes endometrial cells constantly expose to high concentration of oxygen. When endometrial tissues shed off from the eutopic uterus and retrograde to the peritoneal cavity, they face severe hypoxic stress. Even with successful implantation to ovaries or peritoneum, the hypoxic stress remains as a critical issue because endometrial cells are used to live in the welloxygenated environment. Under the hypoxia condition, cells undergo epigenetic modulation and evolve several survival processes including steroidogenesis, angiogenesis, inflammation and metabolic switch. The complex gene regulatory network driven by hypoxia ensures endometriotic cells can survive under the hostile peritoneal microenvironment. Conclusion: Hypoxia plays critical roles in promoting pathological processes to facilitate the development of endometriosis. Targeting hypoxia-mediated gene network represents an alternative approach for the treatment of endometriosis.

TET1 may contribute to hypoxia-induced epithelial to mesenchymal transition of endometrial epithelial cells in endometriosis

“…Hypoxia is an important factor of the endometriosis microenvironment (Becker et al, 2008;Wu, Hsiao & Tsai, 2019). Hypoxia can induce epigenetic changes in tumor cells, whereas hypoxia-induced epigenetic changes in endometriosis haven't been reported yet (Zhou et al, 2006;Shahrzad et al, 2007).…”

Tetraspanin 1 promotes endometriosis leading to ovarian clear cell carcinoma

“…During this process, endometriosis is formed through complex survival processes such as steroidogenesis, angiogenesis, inflammation, and metabolic switches [41]. To withstand the hypoxic conditions, complex gene regulation is involved in endometriosis development [41]. Hypoxia is the main stimulus that activates AMPK [42,43].…”

Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells

“…Second, through the use of both in vitro and in vivo studies, we have provided convincing evidence that platelets are an unindicted culprit responsible for increased local production of estrogen, and that this is mainly through the induction of NF-κB and TGF-β1 signaling pathways. Third, our study provides evidence that activated platelets can directly induce a hypoxia state in endometriotic lesions, which subsequently cause further phenotypic changes 39 . Lastly, this study further underscores the importance of lesional microenvironment in shaping its fate.…”

“…These findings in wound healing raise a question as whether culprits other than endometriotic cells in the lesional microenvironment could also be responsible for the increased local estrogen production. Recent studies have shown that hypoxia, occurred to menstrual debris that is devoid of blood supply when regurgitated into the peritoneal cavity, can dramatically turn endometrial stromal cells into endometriotic counterpart, causing completely different phenotypes 39 . This notion may explain as why endometrial debris may invade and then establish itself in ectopic sites.…”