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Graduate Institute of Basic Medical Sciences (Y.-J.L., L.-Y.C.W.) and Departments of Immunology (H.-Y.L.) and Physiology (L.-Y.C.W.), Medical College, National Cheng Kung University, Tainan 70101, Taiwan; and Department of Physical Therapy (M.-D.L.), Shu-Zen College of Medicine and Management, Kaohsiung 82144, Taiwan
Address all correspondence and requests for reprints to: Lih-Yuh C. Wing, Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan. E-mail: wing{at}mail.ncku.edu.tw.
Substantial evidence suggests that inflammatory cytokines, immune cells, and angiogenesis are important for endometriosis. In this study, we investigated the role of the sequential events in the development of endometriosis in a mouse model. Uterine tissue was transplanted into the peritoneum of ovariectomized mice and then supplemented with estrogen or vehicle. On different days after transplantation, cell proliferation, angiogenesis, and infiltrated immune cells in ectopic tissue were examined using immunochemical staining. Many disintegrated blood vessels but no bromodeoxyuridine-positive cells in ectopic tissue were observed in the estrogen-treated group on posttransplantation d 1 and 2. On d 4–7, bromodeoxyuridine-positive cells were detected in the blood vessels of ectopic tissue, indicating that angiogenesis was initiated in this stage. Angiogenesis also occurred in ectopic tissue in the vehicle-treated group. Profound infiltration of neutrophils in ectopic tissue occurred on d 1–4, when the number of neutrophils and levels of macrophage inflammatory protein (MIP)-1
and MIP-2 chemokines in peritoneal fluids also reached their peak. Peritoneal macrophage numbers did not change, but secretions of TNF, IL-6, MIP-1, and MIP-2 from macrophages isolated on d 2 were higher than on d 0. In vitro studies showed that peritoneal neutrophils and macrophages secreted vascular endothelial growth factor, which was up-regulated by TNF and IL-6. Our results suggest that neutrophils and macrophages may promote angiogenesis in the early stage of endometriosis and that chemokines and cytokines amplify the angiogenic signal for the growth of endometriotic tissue.
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