Abstract
BackgroundAngiogenesis is an essential process in endometriosis disease progression. Earlier, we demonstrated that anti-angiogenic peptide, ABT-898 prevents neoangiogenesis of human endometriotic lesions in a xenograft mouse model. Since angiogenesis is essential for normal ovarian and uterine function, we evaluated effects of ABT-898 on normal female reproductive processes in mice.MethodsCycling female C57BL/6N mice were dosed with ABT-898 (100 mg/kg) or 5 % dextrose control for 21 consecutive days to cover multiple estrous cycles (average estrous cycle 4 to 5 days in mice). Pregnant female mice were dosed with ABT-898 (100 mg/kg) or control on alternate days over the course of gestation, beginning at gestation day 7.5 to 17.5 (gestation length 21 days). Histological analysis along with CD31 and Vimentin immunohistochemistry were performed on ovaries and uteri obtained from treated and control mice. To understand the influence of ABT-898 on systemic angiogenic factors, a Pro Mouse Cytokine 9-plex assay was performed on plasma samples obtained from mice prior to treatment, during the second week of ABAT-898 or control treatment and on the last day of treatment.ResultsABT-898 did not affect the number of estrous cycles over the 21 day treatment compared to control. Histological analysis of ovaries found no difference in the number of primordial, primary, secondary, and antral follicles between ABT-898 treated and control groups. Similarly, no difference was observed in the microvessel density between ABT-898 treated and control uteri, ovarian follicles or corpus luteum when assessed using CD31 or vimentin immunohistochemistry. Electron microscopy revealed similar capillary structure and appearance in both ABT-898 treated and control uteri. Although peripheral blood angiogenic cytokine profiles (IL-15, IL-18, M-CSF, b-FGF, PDGF-bb, MIG, MIP-2, LIF and VEGF) changed over the course of the intervention, there was no significant difference between ABT-898 and control groups at any of the studied time points. Treatment with ABT-898 during pregnancy had no effect on litter size at birth, pup weight at birth or pup weight at weaning.ConclusionOur findings suggest that ABT-898 may not alter angiogenesis dependent reproductive processes in female mice. However, an extensive reproductive toxicology screening is required to substantiate use of ABT-898 in future.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-016-0192-7) contains supplementary material, which is available to authorized users.
Highlights
Angiogenesis is an essential process in endometriosis disease progression
Using an alymphoid xenograft mouse model [13], we have previously demonstrated that the anti-angiogenic peptide ABT-898, a thrombospondin-1 (TSP-1) mimetic, prevents the neovascularization of human endometriotic lesions in mice
Since angiogenesis is integral in normal physiological processes, in this study we examined the chronic effect of ABT-898 on angiogenesis dependent reproductive processes in both non-pregnant cycling and pregnant female mice
Summary
Angiogenesis is an essential process in endometriosis disease progression. Since angiogenesis is essential for normal ovarian and uterine function, we evaluated effects of ABT-898 on normal female reproductive processes in mice. Endometriosis, the growth of endometrial glands and stroma outside of the uterus, is a disease that causes dyspareunia, dysmenorrhea, and pelvic pain. The formation and survival of endometriosis lesions requires the development of a complex vascular network to meet the metabolic demands of the growing tissue. This is achieved by angiogenesis, the formation of new blood vessels from pre-existing blood vessels (reviewed in [3]). Anti-angiogenic therapy is a potential promising way to medically manage endometriosis disease progression
Sign-in/Register to view highlights & summary 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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
