Effect of Vascular Endothelial Growth Factor Inhibition on Endometrial Implant Development in a Murine Model of Endometriosis

Abstract

The main factor involved in neovascularization of ectopic endometrial tissue in endometriosis is the vascular endothelial growth factor (VEGF), which is produced both by the endometrial implant and by peritoneal macrophages. On the other hand, bevacizumab is an antiangiogenic agent used in the treatment of different tumors, like colorectal, pulmonary, and recently mammary. We evaluated the effect of the inhibition of VEGF activity with bevacizumab (Avastin) on ectopic endometrial growth in a murine model of endometriosis. Two months old female BALB/c mice had surgery performed to induce endometriotic-like lesions. Treatment with bevacizumab started on post-surgery day 15 and continued during 2 weeks. Then, animals were sacrificed, peritoneal fluid was collected, and endometriotic-like lesions were counted, measured, and removed. Cell proliferation, vascular density, and apoptosis were assessed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), immunohistochemistry for CD34, and Terminal Deoxynucleotidil Transferase-Mediated dUTP Nick End Labeling (TUNEL), respectively. Vascular endothelial growth factor levels were evaluated in the peritoneal fluid by enzyme-linked immunoassay (ELISA). Treatment with bevacizumab significantly inhibited endometriotic lesion development (P < .05). Consistently, bevacizumab significantly inhibited cell proliferation in lesions (P < .01), reduced vascular density (P < .001), as well as increased the apoptotic cell percentage (P < .001). In addition, bevacizumab reduced VEGF levels in peritoneal fluid of endometriosis-induced animals (P < .05). In conclusion, this study suggests a direct effect of bevacizumab on the reduction of endometrial implant growth and supports further research on VEGF inhibition as a novel therapeutic modality in endometriosis.

The Non-Ergot Derived Dopamine Agonist Quinagolide as an Anti-Endometriotic Agent

“…Post-treatment levels of VEGF and IL-6 in the peritoneal fluid were significantly lower in the quinagolide group when compared with pre-treatment levels. Increasing evidence suggests the VEGF family may be involved with formation, persistence and progression of endometriosis by inducing angiogenesis neovascularization [5,16]. All these findings indicate there is a regressing effect of quinagolide on experimental endometriosis.…”

Pharmacologic therapies in endometriosis: a systematic review

“…As in human endometriosis, very few blood vessels of lesions from this model are covered by pericytes (67). The use of VEGF antibody was associated with statistically significantly reduced cell proliferation in lesions, increased apoptotic index, and reduced vascular density and VEGF concentration in peritoneal fluid (69). It was also capable of reducing lesion size, either when administered immediately after the grafting of the explants (67) or when given 2 to 3 weeks later after endometriotic lesions were already stable (68,69).…”

“…The use of VEGF antibody was associated with statistically significantly reduced cell proliferation in lesions, increased apoptotic index, and reduced vascular density and VEGF concentration in peritoneal fluid (69). It was also capable of reducing lesion size, either when administered immediately after the grafting of the explants (67) or when given 2 to 3 weeks later after endometriotic lesions were already stable (68,69). This suggests that neoangiogenesis is important not only for endometriotic lesion establishment, but also remains relevant for its maintenance and growth.…”

“…Antihuman VEGF-A antibodies and soluble flt-1, a truncated VEGF-A receptor that competes with VEGFR-2 for VEGF binding, have been tested as inhibitors of neoangiogenesis and endometriotic lesion formation in the mouse model (67,68,69). As in human endometriosis, very few blood vessels of lesions from this model are covered by pericytes (67).…”

The role of stem cells in the pathogenesis of endometriosis (а review)

“…Лечение сорафенибом (BAY 43-9006), инги-битором тирозинкиназ рецепторов VEGF, привели к снижению пролиферации и миграции клеток ММСК, полученных из эктопического эндометрия, а также к уменьшению размера очагов эндометриоза у крыс [48,54]. Снижение активности и роста очагов эндометриоза аналогичным образом было отмечено на моделях животных с использованием бевацизума-ба (анти-VEGF моноклональных антител), SU6668 и SU5416 (ингибиторов тирозинкиназы VEGF рецеп-тора 2 [6,54,55].…”