Neutrophils and Macrophages Promote Angiogenesis in the Early Stage of Endometriosis in a Mouse Model

Abstract

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)-1alpha and MIP-2 chemokines in peritoneal fluids also reached their peak. Peritoneal macrophage numbers did not change, but secretions of TNFalpha, IL-6, MIP-1alpha, 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 TNFalpha 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.

Macrophages Are Alternatively Activated in Patients with Endometriosis and Required for Growth and Vascularization of Lesions in a Mouse Model of Disease

“…Macrophages deliver trophic and antiapoptotic signals, in particular during the very first days after endometrium injection, 40 before the formation of novel vessels, 36,41,42 which possibly facilitate the survival of ectopic cells in a relatively hypoxic environment. 40 Endometriotic macrophages are actively involved in both i) the phagocytic clearance of aged red cells 20,38 and endometrial cell debris, 43 and ii) the secretion of trophic and neo-angiogenic molecules. These features are typical of macrophages that have acquired an alternatively activated phenotype.…”

Lipocalin 2 induces the epithelial–mesenchymal transition in stressed endometrial epithelial cells: possible correlation with endometriosis development in a mouse model

“…Autotransplantations were carried out as described by Somigliana et al (1999) and Lin et al (2006) with modifications. Female ICR mice (6 weeks old) were ovariectomized (day 0) and then s.c. injected with estrogen (15 mg/mouse) on days 0 and 3.…”

Circadian rhythms of angiogenic factors in skin and wound tissue in per2-mutant mice

“…VEGF has been known to play an important role in the wound healing process. Leucocytes are known to be one of the sources of VEGF [17]. Our previous study showed the presence of VEGF in leucocytes [1].…”