losartan-potassium and Endometriosis

The development of endometriotic lesions is crucially dependent on the formation of new blood vessels. In the present study, we analysed whether this process is regulated by erythropoietin-producing hepatoma receptor B4 (EphB4) signalling.. We first assessed the anti-angiogenic action of the EphB4 inhibitor NVP-BHG712 in different in vitro angiogenesis assays. Then, endometriotic lesions were surgically induced in the dorsal skinfold chamber and peritoneal cavity of NVP-BHG712- or vehicle-treated BALB/c mice. This allowed to study the effect of EphB4 inhibition on their vascularisation and growth by means of intravital fluorescence microscopy, high-resolution ultrasound imaging, histology and immunohistochemistry.. Non-cytotoxic doses of NVP-BHG712 suppressed the migration, tube formation and sprouting activity of both human dermal microvascular endothelial cells (HDMEC) and mouse aortic rings. Accordingly, we also detected a lower blood vessel density in NVP-BHG712-treated endometriotic lesions. This was associated with a reduced lesion growth due to a significantly lower number of proliferating stromal cells when compared to vehicle-treated controls.. Inhibition of EphB4 signalling suppresses the vascularisation and growth of endometriotic lesions. Hence, EphB4 represents a promising pharmacological target for the treatment of endometriosis.

Topics: Animals; Carcinoma, Hepatocellular; Endometriosis; Endothelial Cells; Erythropoietin; Female; Humans; Liver Neoplasms; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Receptor, EphB4

Endometriosis is a benign gynaecological disease, affecting women during their reproductive years. Angiogenesis represents a crucial step in the pathogenesis of endometriosis, because endometriotic lesions require neovascularization. In this study several angiogenesis-related genes have been studied in the context of endometriosis. Some of the analyzed angiogenic factors as well as their interactions were studied the first time regarding a possible association with endometriosis.. This case-control study consisted of 205 biopsies of 114 patients comprising 61 endometriosis patients and 53 control patients. Among them in 29 cases paired samples were obtained. VEGFA, VEGFR2, HIF1A, HGF, NRP1, PDGFB, FGF18, TNFα, TGFB2, EPHB4, EPO and ANG mRNA expression was analyzed by qRT-PCR in ectopic tissue samples, in eutopic endometrium of women with and without endometriosis, and in unaffected peritoneum of women with and without endometriosis.. VEGFR2, HIF1A, HGF, PDGFB, NRP1 and EPHB4 are overexpressed in ectopic lesions compared to eutopic tissues. VEGFR2, HGF, PDGFB, NRP1, and EPHB4 showed highest mRNA levels in peritoneal implants, in contrast HIF1A showed the highest expression in ovarian endometriomas. Correlation analyses of angiogenic factors in ectopic lesions revealed the strongest associations between VEGFR2, PDGFB, and EPHB4. We further showed a significant upregulation of VEGFR2, HIF1A and EPHB4 in eutopic endometrium of women with endometriosis compared to that of controls and a trend towards upregulation of HGF. Additionally, a significant downregulation for HIF1A, HGF and EPHB4 was observed in unaffected peritoneal tissues of women with endometriosis compared to controls.. We identified new genes (EPHB4 and NRP1) that may contribute to angiogenesis in endometriosis beside known factors (VEGFA, VEGFR2, HIF1A, HGF, and PDGFB). Correlation studies revealed the putative importance of EBHB4 in association with endometriosis. Our analyses support preliminary reports that angiogenic factors seem to be differently expressed in peritoneal implants, ovarian endometriomas and deep infiltrating endometriosis. Our observation that angiogenic factors are differently expressed in the unaffected peritoneum of women with endometriosis compared to women without endometriosis underlines the importance of the peritoneum in the establishment of endometriosis.

Topics: Adult; Case-Control Studies; Endometriosis; Endometrium; Erythropoietin; Female; Fibroblast Growth Factors; Hepatocyte Growth Factor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neovascularization, Pathologic; Neuropilin-1; Proto-Oncogene Proteins c-sis; Receptor, EphB4; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Topics: Adult; Ascitic Fluid; Endometriosis; Erythropoietin; Female; Humans; Peritoneum; Vascular Endothelial Growth Factor A

Recent studies have indicated new physiological roles for erythropoietin (Epo) unrelated to erythropoiesis. We previously demonstrated that the Epo concentrations in peritoneal fluid from patients with stage I endometriosis were significantly higher than those with stages II, III and IV of the disease. Therefore, we hypothesized that Epo may play a role in the pathogenesis of endometriosis, particularly during the early stages of the disease.. We investigated the localization of Epo and the Epo receptor (Epo-R) in peritoneal endometriosis and eutopic endometrium, using immunohistochemistry.. We detected Epo and Epo-R localized within glandular epithelial cells in both peritoneal endometriosis and eutopic endometrium. There was no significant difference in Epo expression between red and black peritoneal lesions, whereas Epo-R expression was significantly lower in black peritoneal lesions when compared to red lesions. Epo and Epo-R expression levels within red peritoneal lesions were comparable to those of eutopic endometrium from patients with endometriosis.. The present findings suggest that Epo may play a role in the pathophysiology of endometriosis.

Topics: Adult; Endometriosis; Endometrium; Erythropoietin; Female; Humans; Immunohistochemistry; Peritoneal Diseases; Receptors, Erythropoietin; Tissue Distribution

Erythropoietin (Epo) is an important regulator of erythropoiesis and stimulates the proliferation of early erythroid precursors as well as the differentiation of late erythroid precursors of the erythroid lineage. However, recent studies have indicated that Epo also has angiogenic properties and plays an important role in the oestrogen-dependent cyclical angiogenesis within the mouse uterus. It was therefore postulated that Epo may be an important angiogenic factor in endometriosis. In order to address this hypothesis the concentration of Epo in peritoneal fluid (PF) was determined in patients with or without endometriosis. PF was collected from patients with endometriosis (n = 42) or without endometriosis (n = 18). Detectable concentrations of Epo were found in all PF samples analysed. The concentration of Epo in PF from patients with endometriosis was significantly higher than that in the control group (13.1 +/- 1.2 mIU/ml versus 7.2 +/- 0.7 mIU/ml, mean +/- SE respectively, P < 0.01). Furthermore, in patients with endometriosis the Epo concentrations in PF from patients with stage I disease (n = 17, 16.6 +/- 3.0 mIU/ml) were significantly higher than those with stage II (n = 8, 10.7 +/- 1.2 mIU/ml, P < 0.03), III (n = 13, 8.4 +/- 1.0 mIU/ml, P < 0.01), IV disease (n = 7, 7.5 +/- 1.0 mIU/ml, P < 0.01). These data suggest that Epo may play a role in the pathogenesis of endometriosis particularly in the initiation of the disease.

Topics: Adult; Ascitic Fluid; Endometriosis; Erythropoietin; Female; Humans; Reference Values