Inhibition of Cyclooxygenase-2 Suppresses the Recruitment of Endothelial Progenitor Cells in the Microvasculature of Endometriotic Lesions

Abstract

The incorporation of endothelial progenitor cells (EPCs) into newly developing blood vessels contributes to the vascularization of endometriotic lesions. We analyzed whether cyclooxygenase (COX)-2 signaling regulates this vasculogenic process. Endometriotic lesions were surgically induced in irradiated FVB/N mice, which were reconstituted with bone marrow from FVB/N-TgN [Tie2/green fluorescent protein (GFP)] 287 Sato mice. The animals received β-estradiol 17-valerate once a week and were treated daily with the selective COX-2 inhibitor parecoxib (25 mg/kg) or vehicle (control) for 7 and 28 days. Analyses involved the determination of lesion growth, cyst formation, homing of GFP/Tie2 EPCs, numbers of circulating EPCs, vascularization, cell proliferation, apoptosis, and immune cell infiltration by means of high-resolution ultrasonography, caliper measurements, flow cytometry, histologic analysis, and immunohistochemical analysis. In parecoxib-treated mice, blood circulating EPCs were higher, but numbers of recruited EPCs in endometriotic lesions were significantly lower when compared with controls. This finding was associated with an impaired early vascularization and stromal tissue growth as well as reduced glandular secretory activity of the lesions. Parecoxib-treated lesions further contained less proliferating and more apoptotic cells and exhibited lower numbers of infiltrating macrophages and neutrophilic granulocytes. These findings demonstrate that the inhibition of COX-2 suppresses vasculogenesis in endometriotic lesions, which may contribute to an impaired lesion vascularization and growth.

Endothelial Progenitor Cells: New Targets for Therapeutics for Inflammatory Conditions With High Cardiovascular Risk

“…This is mirrored in coronary heart disease, reinforcing the connections between ECFC dysfunction, aging, and cardiovascular risk ( 28 ). However, there are also reports that bone-marrow derived progenitor cell numbers remain stable, suggesting that, in some cases, the decline in reparatory ability may be due to cellular impairments, in their homing, angiogenic capacity or their propensity for senescence and premature cell death ( 28 , 30 , 31 ). Studies have shown that late ECFCs from elderly volunteers demonstrate impaired migration, proliferation and adhesion properties compared to those from young participants ( 29 , 32 , 33 ), and show a reduced capacity for re-endothelialization and incorporation into a damaged vasculature ( 29 ).…”

Inhibition of erythropoietin‐producing hepatoma receptor B4 (EphB4) signalling suppresses the vascularisation and growth of endometriotic lesions

“…This observation can be explained by the fact that the engraftment of the transplanted uterine tissue is already completed at this late time point. Accordingly, this phase of lesion development is rather characterised by vessel maturation and remodelling than by extensive angiogenesis and cell turnover (Rudzitis‐Auth, Nenicu, Nickels, Menger, & Laschke, 2016; Rudzitis‐Auth, Nickels, Menger, & Laschke, 2018). Therefore, we performed additional analyses of peritoneally transplanted uterine tissue on Day 7 and detected a reduced microvessel density and stromal cell proliferation within NVP‐BHG712‐treated lesions when compared to controls.…”

“…For the in vivo experiments, the group sizes were chosen according to previous studies using the herein described endometriosis models (Feng, Menger, & Laschke, 2013; Rudzitis‐Auth, Nenicu, Nickels, Menger, & Laschke, 2016; Rudzitis‐Auth, Nickels, Menger, & Laschke, 2018). Data were first analysed for normal distribution and equal variance.…”

“…For the qRT-PCR analyses, the measured values were corrected to control group values by data normalisation to reduce the variation between independent experiments. For the in vivo experiments, the group sizes were chosen according to previous studies using the herein described endometriosis models (Feng, Menger, & Laschke, 2013;Rudzitis-Auth, Nenicu, Nickels, Menger, & Laschke, 2016;Rudzitis-Auth, Nickels, Menger, & Laschke, 2018). Data were first analysed for normal distribution and equal variance.…”

Hemodynamic forces enhance decidualization via endothelial-derived prostaglandin E2 and prostacyclin in a microfluidic model of the human endometrium

“…Furthermore, our findings revealed the identity of key prostaglandins activated during early decidualization, potentially offering an opportunity to target these molecules for therapeutic development. Clinically, targeting specific terminal prostaglandin species, may provide a putative non-steroidal solution to alleviate pain and chronic inflammation for certain reproductive disorders, while maintaining or restoring endometrial receptivity (Lee et al , 2013; Laux-Biehlmann et al , 2015; Rudzitis-Auth et al , 2018). Thus, revisiting the role of specific prostaglandins and their receptors that may be critical for reproductive function of both the gravid and non-gravid uterus is appropriate.…”