Compatibility of a Novel Thrombospondin-1 Analog with Fertility and Pregnancy in a Xenograft Mouse Model of Endometriosis

Diane S Nakamura, Andrew K Edwards, Soo Hyun Ahn, Richard Thomas, Chandrakant Tayade
PloS one · 2015 · vol. 10(3) , pp. e0121545 · doi:10.1371/journal.pone.0121545 · PMID:25811892 · W2031417007
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Abstract

Endometriosis is a gynecological disease defined by the growth of endometrium outside of the uterus. Although endometriosis contributes to 50% of female infertility cases, medical treatments are incompatible with pregnancy. Angiogenesis, the growth of blood vessels from existing vasculature, plays a crucial role in endometriotic lesion growth and survival. Previously, we demonstrated the effectiveness of thrombospondin-1 analog, ABT-898 (Abbott Laboratories) to inhibit endometriotic lesion vascularization in mice. We have now evaluated the trans-generational implications of ABT-898 treatment before and during mouse pregnancy. We hypothesized that ABT-898 would target lesion vasculature without affecting pregnancy, offspring development, or ovarian and uterine vascularity in mice. Endometriosis was induced using human endometrium in β-estradiol-primed BALB/c-Rag-2-/-Il2rγ-/- mice receiving intraperitoneal injections of ABT-898 (25 mg/kg) or 5% dextrose control for 21 days. Ultrasound assessment of lesion vascularization revealed a reduction in blood flow supplying treated lesions. Excised ABT-898 treated lesions stained for CD31+ endothelial cells exhibited a decrease in microvessel density. Following confirmation of estrous cycling, mice were bred and treated with ABT-898 on gestation days 7, 9, 11, 13, 15, 17, and 19. ABT-898 did not affect estrous cycling or pregnancy parameters including litter size across generations and offspring weight gain. Quantification of angiogenic cytokine plasma levels revealed no significant differences between treatment groups. Vimentin staining of the uterus and ovary revealed no observable effects of ABT-898. Similarly, no obvious histological anomalies were observed in the kidney, liver, ovary, or uterus following ABT-898 treatment. These results suggest that ABT-898 effectively inhibit endometriotic lesion vascularization without affecting trans-generational pregnancy outcomes in mice.

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mesh:D004715endometriosisinfertility

MeSH descriptors

Endometriosis Endometriosis Thrombospondin 1 Animals Cytokines Cytokines Cytokines Disease Models, Animal Endometriosis Endometriosis Endometriosis Endometriosis Endothelial Cells Endothelial Cells Estrous Cycle Female Fertility Fertility Heterografts Humans

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