Extracellular vesicle-associated VEGF-C promotes lymphangiogenesis and immune cells infiltration in endometriosis.

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.

"Silent" rupture of unscarred gravid uterus with subsequent pelvic abscess: successful laparoscopic management.

Intrapartum rupture of an unscarred uterus is rare in current times. However, it is still associated with significant maternal and fetal mortality and morbidity. Unlike rupture or dehiscence of a previous cesarean scar, which is occasionally bloodless, complete rupture of a gravid unscarred uterus frequently results in fetal jeopardy and significant maternal intraperitoneal bleeding, causes acute abdomen, and demands emergency surgical (laparotomy) intervention. Laparoscopy generally has no role in such circumstances due to the generally unstable maternal hemodynamic condition and the necessity of prompt fetal delivery with an abdominal approach. We present a rare case of intrapartum rupture of an unscarred gravid uterus with an atypical insidious clinical course. The diagnosis of complete uterine rupture was made 20 days after the patient's successful vaginal delivery, at which time a large pelvic abscess formed. The condition was successfully managed laparoscopically. Successful vaginal delivery, even with normal lochia, good uterine contraction, and stable vital signs, does not preclude the possibility of uterine rupture. For patients with unusual postpartum pelvic pain, uterine rupture should be considered as one of the possible etiologic factors, and prompt survey should be performed. Laparoscopic intervention may be valuable in such situations.