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Abstract
Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment.
Highlights
Endometriosis is a reproductive age-associated disease characterized by the presence of endometrial-like tissue outside the uterus [1,2]
We evaluated the effects of quinagolide treatment on relevant functional characteristics of eutopic and ectopic Endometrial mesenchymal stromal cells (E-MSCs) lines, isolated from normal endometrium or endometriotic lesions, including proliferation, invasion and endothelial differentiation, and the related molecular mechanisms involved
All E-MSC lines were positive for specific endometriotic mesenchymal stem cell markers sushi domain containing-2 (SUSD2) and PDGFRb (CD140b), with lower expression by ectopic E-MSCs with respect to eutopic ones, suggesting that E-MSCs represent a heterogenic population of mesenchymal stem cells and stromal fibroblasts, sharing a number of markers and functions
Summary
Endometriosis is a reproductive age-associated disease characterized by the presence of endometrial-like tissue outside the uterus [1,2]. We previously isolated E-MSCs from endometriotic lesions and showed their increased pro-angiogenic properties, including VEGF release, with respect to eutopic E-MSCs and the related inhibitory effect of a tyrosine kinase inhibitor, Sorafenib [21]. In this context, dopamine and its receptor agonists may represent an alternative to current anti-angiogenic agents due to the inhibition of VEGF release and VEGF receptor 2 (VEGFR-2) activation [22]. We evaluated the effects of quinagolide treatment on relevant functional characteristics of eutopic and ectopic E-MSC lines, isolated from normal endometrium or endometriotic lesions, including proliferation, invasion and endothelial differentiation, and the related molecular mechanisms involved
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