The Role Of Hypoxia In Endometriosis And Its Pathogenic Mechanism

Backgroud: Endometriosis (EMs) is a kind of modern gynecological diseases. Itsmorbidity reaches an estimated6%to10%of women at reproductive ages, and thisprevalence increases up to30%in women with infertility. EMs shows stronglyassociated with the increased risk of ovarian clear cell and endometrioid subtypes ofepithelial ovarian cancer.Sampson’s theory of reflux menstruation is almost consistent with numerousempirical evidence since1927. EMs occurs in only a few females while most femalesdemonstrate reflux menstruation. Recently the abnormal eutopic endometriumdeterminism renews and develops the classic theory, but there is no further reportsthat how and when the eutopic endometrium grow into EMs. In nature, EMs is closelyrelated to the menstruation, which is in ischemic and hypoxic state until angiogenesisin the pelvic cavity during menstruation reflux. In fact, recent experimental andclinical studies have suggested that hypoxia affected a series of biological parametersinfluencing the malignant potential of the neoplasm. The invasion and metastasis andrecurrence features of EMs were similar to the biological behavior of neoplasm.Therefore, it may be a new idea for EMs diagnosis and treatment to explore the roleof hypoxia in EMs pathogenesis.Objective: To investigate the effects of chronic and acute hypoxia on the proliferationand apoptosis and angiogenesis of the endometrial cell and tissue. To study theimplants from the eutopic and ectopic endometrial tissue and the implants locatedsubcutaneously or intraperitoneal in the SCID mice, and the expression of hypoxiainducible factor, angiogenesis and adhesion relevant peptide in the implants. Methods: The eutopic endometrium from EMs symptomatic women and controlwomen were collected and treated with chronic and acute hypoxia in vitro. EMs wasinduced in the SCID mice by subcutaneously or intraperitoneal heterograft of eutopicendometrium in vivo. Immunofluorescence cytochemistry, Flow Cytometry Analysis,Hematoxylin-eosin staining and immunohistochemical technique, Western blot andELISA methods were performed to examine the expression of angiogenesis, apoptosis,hypoxia inducible factor, angiogenesis and adhesion relevant peptide in the implants.Results:1.Hypoxic culture up-regulated the glandular and stroma endometrialepithelium apoptosis than normoxic culture. However, the hypoxic EMs cellsexhibited affluent pseudopods and expressed more ki67and HIF-1αand VEGF thanthe normoxic control group.2.The weight of the EMs implants from hypoxiapreteatment group were significantly increased compared with the normoxia andhypoxia preteatment group, and the expression of MVD、HIF-1α、VEGF and Ki67also increased in the hypoxia preteatment group than the other groups.3. Eutopic andectopic and control implants grew differently in SCID mice model. The weight andthe expression of HIF-1α, CD34, VEGF and CA125of the grafts and the CA125levels in animal ascites were increased significantly in the ectopic group than eutopicand control group.4. Adhesion bands occurred more in the i.p. group than the s.c.group and the control group, but the graft volume changes and the expression ofMMP-2,TIMP-2,MVD,VEGF and HIF-1α increased significantly in the s.c. groupthan the i.p. group.Conclusions:1. Hypoxia can induce apoptosis of endometriotic cells but also inducecell proliferation and angiogenesis.2. Acute and chronic hypoxia might change EMsbiological behavior and this might have a direct effect on the treatment of EMs.3.Ectopic endometrial tissue have higher potential to survive and possibly implant,which might be the results of eutopic endometrium selected by hypoxia.4. Theadhesion and angiogenesis of the EMs grafts in varying location of the SCID micegrew differently, and this might be association with local hypoxic microenvironment.