Ding Ding1, Xishi Liu2, Jie Duan1, Sun-Wei Guo3. 1. Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China. 2. Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China. 3. Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China hoxa10@outlook.com.
Abstract
STUDY QUESTION: Do platelets play any role in the development of endometriosis? SUMMARY ANSWER: Activated platelets aggregate in endometriotic lesions and play important roles in the development of endometriosis. WHAT IS KNOWN ALREADY: Platelets play important roles in cancer development and metastasis but there is no published study on their role in the development of endometriosis, even though endometriotic lesions undergo repeated cycles of tissue injury and repair, which characteristically involve platelets. STUDY DESIGN, SIZE, DURATION: Cross-sectional clinical studies of women with and without endometriosis, in vitro experimentation, and animal studies using platelet and/or macrophage depletion. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunohistochemistry analysis of ectopic/eutopic endometrial tissues from 58 women with and 47 without endometriosis. Proliferation assay, cell cycle analysis by flow cytometry, gene expression and protein analysis for COX-2, VEGF, MMP-9, and Bcl-2 using primary cell culture, and evaluation of the rate of platelet activation induced by peritoneal fluid from women with and without endometriosis. Two mouse experiments, one that evaluated the effect of platelet depletion on lesion development and its associated phenotypic changes, and the other, the effect of platelet and/or macrophage depletion. MAIN RESULTS AND THE ROLE OF CHANCE: We found that platelets aggregated in endometriotic lesions, concomitant with elevated VEGF expression and microvessel density. Co-culture of endometriotic stromal cells with platelets enhanced cellular proliferation, and increased the expression of COX-2, MMP-9, VEGF, and Bcl-2. IL-1β-induced COX-2 up-regulation and increased production of the coagulant TXA(2) in endometriotic stromal cells. Tissue factor (TF) expression was elevated in endometriosis and TF concentrations were significantly elevated both in the supernatant of cultured primary endometriotic stromal cells and in peritoneal fluid from women with endometriosis. Platelet depletion resulted in significantly reduced lesion size and improved hyperalgesia in mice with induced endometriosis. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its cross-sectional design and by its focus on ovarian endometriomas. WIDER IMPLICATIONS OF THE FINDINGS: The demonstration that platelets are involved in the development of endometriosis provides a rationale for the use of anti-coagulants to treat endometriosis, and opens prospects for developing novel biomarkers for diagnostic or prognostic purposes. STUDY FUNDING/COMPETING INTERESTS: Financial support for this study was provided by grants from the National Science Foundation of China, a grant from the Shanghai Science and Technology Commission, support from the Key Specialty Project of the Ministry of Health, People's Republic of China. None of the authors has any conflict of interest to disclose.
STUDY QUESTION: Do platelets play any role in the development of endometriosis? SUMMARY ANSWER: Activated platelets aggregate in endometriotic lesions and play important roles in the development of endometriosis. WHAT IS KNOWN ALREADY: Platelets play important roles in cancer development and metastasis but there is no published study on their role in the development of endometriosis, even though endometriotic lesions undergo repeated cycles of tissue injury and repair, which characteristically involve platelets. STUDY DESIGN, SIZE, DURATION: Cross-sectional clinical studies of women with and without endometriosis, in vitro experimentation, and animal studies using platelet and/or macrophage depletion. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunohistochemistry analysis of ectopic/eutopic endometrial tissues from 58 women with and 47 without endometriosis. Proliferation assay, cell cycle analysis by flow cytometry, gene expression and protein analysis for COX-2, VEGF, MMP-9, and Bcl-2 using primary cell culture, and evaluation of the rate of platelet activation induced by peritoneal fluid from women with and without endometriosis. Two mouse experiments, one that evaluated the effect of platelet depletion on lesion development and its associated phenotypic changes, and the other, the effect of platelet and/or macrophage depletion. MAIN RESULTS AND THE ROLE OF CHANCE: We found that platelets aggregated in endometriotic lesions, concomitant with elevated VEGF expression and microvessel density. Co-culture of endometriotic stromal cells with platelets enhanced cellular proliferation, and increased the expression of COX-2, MMP-9, VEGF, and Bcl-2. IL-1β-induced COX-2 up-regulation and increased production of the coagulant TXA(2) in endometriotic stromal cells. Tissue factor (TF) expression was elevated in endometriosis and TF concentrations were significantly elevated both in the supernatant of cultured primary endometriotic stromal cells and in peritoneal fluid from women with endometriosis. Platelet depletion resulted in significantly reduced lesion size and improved hyperalgesia in mice with induced endometriosis. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its cross-sectional design and by its focus on ovarian endometriomas. WIDER IMPLICATIONS OF THE FINDINGS: The demonstration that platelets are involved in the development of endometriosis provides a rationale for the use of anti-coagulants to treat endometriosis, and opens prospects for developing novel biomarkers for diagnostic or prognostic purposes. STUDY FUNDING/COMPETING INTERESTS: Financial support for this study was provided by grants from the National Science Foundation of China, a grant from the Shanghai Science and Technology Commission, support from the Key Specialty Project of the Ministry of Health, People's Republic of China. None of the authors has any conflict of interest to disclose.
Authors: Joel A Mathews; Yan G Ni; Connie Wang; Jon E Peterson; Chad Ray; Xuemei Zhao; Daoyu Duan; Sara Hamon; John Allinson; Martha Hokom; Greta Wegner Journal: AAPS J Date: 2020-01-29 Impact factor: 4.009
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