Abstract
Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression.
Highlights
Endometriosis is an invasive gynecological disorder of reproductive women characterized by the growth of endometrial glands and stroma outside the uterus
The expressions for both vascular endothelial growth factor (VEGF) and VEGFR2 were significantly increased with the advancement of the disease, confirming the involvement of angiogenesis during ovarian endometriosis progression
Our results showed that while tissue inhibitors of metalloproteinases (TIMP)-2 expression decreased with disease severity (Fig 4A and 4B), MT1MMP expression elevated with the progression of the disease (Fig 4A and 4C)
Summary
Endometriosis is an invasive gynecological disorder of reproductive women characterized by the growth of endometrial glands and stroma outside the uterus. The disease is associated with chronic pelvic pain, severe dysmenorrhea, dyspareunia and infertility. Endometriosis affects almost 10–15% of women in reproductive age and 50% of women with infertility [1]. It is believed to be an estrogen-dependent disease [2], the etiology and pathogenesis of endometriosis remains uncertain. According to the widely accepted ‘Sampson’s theory of retrograde menstruation’, endometriosis originates from the debris of endometrial glands. Detached endometrial tissues of menstruation which include endometrial cells, glands, debris etc, reach the peritoneum by retrograde movement to get implanted, followed by acquisition of new blood supply through angiogenesis [3]. Endometriotic growths are supported by the local hormonal and inflammatory microenvironment and further spread over multiple locations within the peritoneum
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call