Thrombospondin-1 Mimetic Peptide ABT-898 Affects Neovascularization and Survival of Human Endometriotic Lesions in a Mouse Model

Nakamura DS, Diane S Nakamura, Andrew K Edwards, Edwards AK, Virani S, Sophia Virani, Thomas R, Richard Thomas, Chandrakant Tayade, Tayade C
The American journal of pathology · 2012 · vol. 181(2) , pp. 570–582 · doi:10.1016/j.ajpath.2012.05.010 · PMID:22727957 · W2067925891
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The thrombospondin-1 mimetic peptide ABT-898 was found to reduce neovascularization and improve lesion survival in a mouse model of human endometriosis.

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Abstract

Endometriosis is a common cause of pelvic pain and infertility in women, and a common indication for hysterectomy, yet the disease remains poorly diagnosed and ineffectively treated. Because endometriotic lesions require new blood supply for survival, inhibiting angiogenesis could provide a novel therapeutic strategy. ABT-898 mimics the antiangiogenic properties of thrombospondin-1, so we hypothesized that ABT-898 will prevent neovascularization of human endometriotic lesions and that ABT-898 treatment will not affect reproductive outcomes in a mouse model. Endometriosis was induced in BALB/c-Rag2(-/-)Il2rg(-/-) mice by surgical implantation of human endometrial fragments in the peritoneal cavity. Mice received daily injections of ABT-898 for 21 days. Flow cytometry was performed to measure circulating endothelial progenitor cells in peripheral blood. Cytokines were measured in plasma samples. Half of the ABT-898-treated and control mice were euthanized to assess neovascularization of endometriotic lesions, using CD31(+) immunofluorescence. The remaining mice were mated and euthanized at gestation day 12. Endometriotic lesions increased circulating endothelial progenitor cells 13 days after engraftment, relative to baseline. Endometriotic lesions from ABT-898-treated mice exhibited reduced neovascularization, compared with controls, and lesions had fewer CD31(+) microvessels. Chronic treatment with ABT-898 did not lead to any fetal anomalies or affect litter size at gestation day 12, compared with controls. Our results suggest that ABT-898 inhibits neovascularization of human endometriotic lesions without affecting mouse fecundity.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Neovascularization, Pathologic Oligopeptides Peptidomimetics Thrombospondin 1 Animals Cell Movement Cell Movement Cell Proliferation Cell Proliferation Cytokines Cytokines Disease Models, Animal Endometriosis Endometriosis Endometriosis Endometrium Endometrium Estrous Cycle

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