Endometriosis is a highly prevalent gynecological disease with severe negative impacts on life quality and financial burden. Unfortunately, there is no cure for this disease, which highlights the need for further investigation about the pathophysiology of this disease to provide clues for developing novel therapeutic regimens. Herein, we identified that vascular endothelial growth factor (VEGF)-C, a potent lymphangiogenic factor, is up-regulated in endometriotic cells and contributes to increased lymphangiogenesis. Bioinformatic analysis and molecular biological characterization revealed that VEGF-C is negatively regulated by an orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII). Further studies demonstrated that proinflammatory cytokines, via suppression of COUP-TFII level, induce VEGF-C overexpression. More importantly, we show that functional VEGF-C is transported by extracellular vesicles (EVs) to enhance the lymphangiogenic ability of lymphatic endothelial cells. Autotransplanted mouse model of endometriosis showed lenvatinib treatment abrogated the increased lymphatic vessels development in the endometriotic lesion, enlarged retroperitoneal lymph nodes, and immune cells infiltration, indicating that blocking VEGF-C signaling can reduce local chronic inflammation and concomitantly endometriosis development. Evaluation of EV-transmitted VEGF-C from patients’ sera demonstrates it is a reliable noninvasive way for clinical diagnosis. Taken together, we identify the vicious cycle of inflammation, COUP-TFII, VEGF-C, and lymphangiogenesis in the endometriotic microenvironment, which opens up new horizons in understanding the pathophysiology of endometriosis. VEGF-C not only can serve as a diagnostic biomarker but also a molecular target for developing therapeutic regimens.

子宫内膜异位症是一种高度流行的妇科疾病，对生活质量和经济负担造成严重的负面影响。不幸的是，目前尚无治愈该病的方法，这突出表明需要对该病的病理生理学进行进一步研究，以为开发新的治疗方案提供线索。在本文中，我们确定了血管内皮生长因子（VEGF）-C（一种有效的淋巴管生成因子）在子宫内膜异位细胞中上调，并有助于增加淋巴管生成。生物信息学分析和分子生物学特征表明，VEGF-C受孤儿核受体鸡卵清蛋白上游启动子转录因子II（COUP-TFII）负调控。进一步的研究表明，促炎细胞因子通过抑制COUP-TFII的水平，诱导VEGF-C过表达。更重要的是，我们显示功能性VEGF-C通过细胞外囊泡（EV）转运，以增强淋巴管内皮细胞的淋巴管生成能力。自体移植子宫内膜异位症的小鼠模型显示，lenvatinib治疗可消除子宫内膜异位症病灶内淋巴管发育的增加，腹膜后淋巴结肿大和免疫细胞浸润，这表明阻断VEGF-C信号传导可减少局部慢性炎症并伴随子宫内膜异位症的发展。对患者血清中EV传播的VEGF-C的评估表明，这是用于临床诊断的可靠无创方法。两者合计，我们确定了子宫内膜异位微环境中炎症，COUP-TFII，VEGF-C和淋巴管生成的恶性循环，这为了解子宫内膜异位症的病理生理学开辟了新的视野。VEGF-C不仅可以用作诊断生物标志物，而且还可以作为开发治疗方案的分子靶标。