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Edited by Scott K. Durum, National Cancer Institute, Frederick, MD, and accepted by Editorial Board Member Tadatsugu Taniguchi August 6, 2020 (received for review November 14, 2019)
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.
Abstract
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: mhwu68{at}mail.ncku.edu.tw or seantsai{at}mail.ncku.edu.tw.
Author contributions: W.-N.L. and S.-J.T. designed research; W.-N.L., K.-Y.H., C.-A.W., N.C., and P.-L.H. performed research; C.-H.S., S.-R.W., and M.-H.W. contributed new reagents/analytic tools; W.-N.L. analyzed data; and W.-N.L. and S.-J.T. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission. S.K.D. is a guest editor invited by the Editorial Board.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1920037117/-/DCSupplemental.
Data Availability.
Microarray data are available at the National Center for Biotechnology Information GEO, accession no. GSE107469. All other study data are included in the article and supporting information.
Published under the PNAS license.
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Extracellular vesicle-associated VEGF-C promotes lymphangiogenesis and immune cells infiltration in endometriosis
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