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Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis.

ABSTRACT: Endometriosis, a chronic disorder characterised by the presence of endometrial-like tissue outside the uterus, is associated with iron overload and oxidative stress in the lesion. Although it is well established that iron overload can trigger ferroptosis, the results of previous studies on ferroptosis resistance and ferroptosis in endometriotic lesions are paradoxical. Here, we found that some stromal cells of the cyst walls that were in contact with the cyst fluid underwent ferroptosis. Surprisingly, endometrial stromal cell ferroptosis triggered the production of angiogenic, inflammatory and growth cytokines. In particular, angiogenic cytokines, such as vascular endothelial growth factor A (VEGFA) and interleukin 8 (IL8), promoted human umbilical vein endothelial cell (HUVEC) vascular formation in vitro. Moreover, we found that inhibition of p38 mitogen-activated protein kinase/signal transducer and activator of transcription 6 (p38 MAPK/STAT6) signalling represses VEGFA and IL8 expression when endometrial stromal cells undergo ferroptosis. Notably, VEGFA and IL8 showed localised expression and were significantly upregulated in ectopic lesions compared to control and eutopic endometrium samples from patients with endometriosis. Thus, our study reveals that endometrial stromal cell ferroptosis in the ovarian endometrioma may trigger cytokine secretion and promote angiogenesis of adjacent lesions via paracrine actions to drive the development of endometriosis, providing a rationale for translation into clinical practice and developing drugs for endometriosis.

SUBMITTER: Li G

PROVIDER: S-EPMC8763888 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis.

Li Guojing G Lin Yu Y Zhang Yili Y Gu Nihao N Yang Bingxin B Shan Shan S Liu Na N Ouyang Jing J Yang Yisai Y Sun Feng F Xu Hong H

Cell death discovery 20220117 1

Endometriosis, a chronic disorder characterised by the presence of endometrial-like tissue outside the uterus, is associated with iron overload and oxidative stress in the lesion. Although it is well established that iron overload can trigger ferroptosis, the results of previous studies on ferroptosis resistance and ferroptosis in endometriotic lesions are paradoxical. Here, we found that some stromal cells of the cyst walls that were in contact with the cyst fluid underwent ferroptosis. Surpris ...[more]

PMID: 35039492

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Project description:Background: Endometriosis (EMs) is the most common gynaecological disorder with its etiology and/or pathophysiology remains enigmatic. Recent studies showed that extracellular vesicles (EVs), exosomes in particular, play a critical role in developing various clinical disorders. However, the implication of exosomes in endometriosis progression has not been well elucidated. Method: The ectopic stromal cellular exosomes (eEVs) were assessed by transwell assay, scratch tests, tube formation assay, western blot, and qRT-PCR analysis. Protein expression profiles of exosomes in endometrial tissue and vaginal discharge collected from patients with EMS and healthy donors were analysed by Mass spectrometry. siRNA interference technology was used to inhibit the expression of exosomal protein for the functional analysis in in-vivo. Finally, in-vitro experiments were performed to validate the results that we observed in EMs mouse model. Results: In vitro, we discovered that eEVs improved NSC migratory potential by upregulating MMP9 expression and activity. eEVs also aided angiogenesis and elevated the expression of inflammatory cytokines in ovarian epithelial cells, according to our findings. Moesin (MSN) levels in ESC exosomes were substantially greater than in NSC exosomes (1.22e8±5.58e6 vs. 6.605e7±4.574e6, LFQ intensity), as shown by protein mass spectrometry and bioinformatics analysis. In ectopic stromal cells, ERa receptors stimulated the RhoA/Rock-2/MSN pathway. We discovered that downregulating exosomal moesin reduced NSC migration (about 3-fold change) and MMP9 expression (about 2-fold change). On the other hand, Exomsni inhibited angiogenesis and inflammatory cytokine release. In vivo the result of immunohistochemistry and immunofluorescence demonstrated that exosomal MSN substantially modified the expression of MM9, VEGFR and p-VEGFR in polyclonal lesions. In addition, we discovered an elevation in the expression of proinflammatory factors in the surrounding tissue. Conclusion: Exosomal MSN derived from ectopic stromal cells can contribute to endometriosis progression by mediating the construction of a "migration-vascularization-inflammation" loop in the ectopic environment.

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Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis.

Publications

Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis.

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