INTRODUCTION: Endometriosis is a common gynaecological disease where endometrial tissue implants in locations ectopic to the uterus. VEZT encodes a transmembrane adherens junction protein known as Vezatin that plays essential roles in pre-implantation embryo development and increased VEZT expression is associated with an increased risk of endometriosis. The aim of this study was to evaluate the functional outcomes of overexpressing VEZT in a unique mouse model of endometriosis.
METHODS: VEZT was overexpressed in human endometrial stromal cell lines followed by RNA-seq and validation of findings qPCR. Immunohistochemistry was used to localise vezatin protein in human endometrium, ectopic lesions and mouse tissues. Following VEZT induction in VEZT-Cre mice, minced donor uterine tissue was injected intraperitoneally into recipient mice. VEZT-Cre and C57/BL6 wildtype (WT) mice received allografts and xenografts recovered at 4 and 8 weeks.
RESULTS: VEZT (vezatin) was significantly increased in secretory phase endometrium and localised to endometrial epithelial cells, decidualised stromal cells, spiral arterioles, inflammatory cells. Vezatin was also upregulated in endometriotic lesion stromal cells, epithelium and vasculature. VEZT overexpression in stromal cells significantly upregulated genes involved with the innate immune system, interferon pathways and cytokines responsible for macrophage recruitment and phenotypic switching. VEZT overexpression in VEZT-Cre mice uterine tissue significantly increased expression of ESR2, CTGF, TGFb and TNFa while significantly reducing PGR expression compared to WT mice. VEZT-Cre mice grafted with uterine fragments for 8 weeks, developed large cystic lesions throughout the peritoneum including the liver, pancreas, ovary, bowel, peritoneum and fat pads while WT lesions regressed.
CONCLUSION: This is the first study of its kind to elucidate several functional roles of the endometriosis risk gene VEZT in endometrial stromal cells, endometriosis lesions and a unique conditional VEZT knock-in mouse model of endometriosis. These findings demonstrate VEZT has the potential as a valuable endometriosis biomarker and therapeutic target.