Significance: Endometriosis is a highly prevalent proinflammatory disease without reliable diagnostic biomarkers and cannot be cured by nowadays’ medical treatments. Herein, we identified that extracellular vesicle (EV)-associated VEGF-C, secreted by proinflammatory cytokine-stimulated endometriotic stromal cells, is a critical modulator for endometriosis progression by promoting lymphangiogenesis. Invaded lymphatic vessels may serve as a canal for the infiltration of immune cells, which further enhances the inflammatory status in the endometriotic microenvironment and produces more EV-VEGF-C. The elevated circulating EV-VEGF-C is a sensitive and reliable biomarker for detecting endometriosis. These data advance our understanding of the pathophysiology of endometriosis and suggest VEGF-C can be a noninvasive diagnostic biomarker and a potential therapeutic target for endometriosis.

How does hypoxia-mediated down-regulation of dual specificity phosphatase-2 (DUSP2) promote endometriotic lesion development? Inhibition of DUSP2 by hypoxia enhances endometriotic lesion growth via promoting interleukin-8 (IL-8)-dependent angiogenesis. Angiogenesis is a prerequisite for the development of endometriosis. DUSP2 is down-regulated in endometriotic stromal cells in a hypoxia inducible factor-1α-dependent manner. Down-regulation of DUSP2 contributes to the pathological process of endometriosis. A laboratory study recruiting 20 patients of reproductive age with endometriosis and normal menstrual cycles, and an autoimplant-induced mouse model of endometriosis using 13 mice in a 28-day treatment. IL-8 mRNA levels were assayed in endometrial stromal cells maintained in normoxic or hypoxic (1% O₂) conditions, with or without DUSP2 knockdown. Promoter activity and chromatin immunoprecipitation (ChIP) assays were conducted to characterize the regulation of IL-8 by DUSP2. Conditioned media from cells maintained in normoxic or hypoxic conditions, and cells with/without DUSP2 knockdown were collected to investigate the angiogenic capacity using an in vitro tube formation assay. Reparixin, an IL-8 receptor blocker, was administered to investigate the role of IL-8 in hypoxia-mediated angiogenesis and the development of endometriotic-like lesions in an autotransplanted mouse model. IL-8 mRNA was increased by both hypoxia and DUSP2 knockdown in endometrial stromal cells in an extracellular signal-regulated protein kinase-dependent manner (P < 0.05 versus control). Promoter activity and ChIP assays demonstrated that expression of IL-8 was regulated by CCAAT/enhancer binding protein α (P < 0.05 versus control). Furthermore, conditioned media collected from hypoxia-exposed or DUSP2 knockdown endometrial stromal cells promoted tube formation, which was abolished by co-treatment with reparixin (P < 0.05 versus control). Results from the autotransplanted mouse model demonstrated that number of blood vessels and size of endometriotic-like lesions were markedly reduced in recipient mice treated with reparixin (P < 0.05 versus control). This study was conducted in primary human cell cultures and a mouse model, therefore may not fully reflect the situation in vivo. This is the first study to highlight the potential application of an IL-8 receptor blocker as a therapeutic target to treat endometriosis. This study demonstrates IL-8 as a key angiogenic factor regulated by hypoxia/DUSP2, which suggests an alternative mechanism through which hypoxia may promote angiogenesis. This study was funded by the National Science Council of Taiwan (NSC101-2314-B-006-043-MY2). The author declares that there is no conflict of interest.

Rationale: Endometriosis is a highly prevalent gynecological disease in women of reproductive age that markedly reduces life quality and fertility. Unfortunately, there is no cure for this disease, which highlights that more efforts are needed to investigate the underlying mechanism for designing novel therapeutic regimens. This study aims to investigate druggable membrane receptors distinctively expressed in endometriotic cells.

Indian J Med Res, Official publication of Indian Council of Medical Research,India