Thrombospondin-1 mimetic peptide ABT-898 affects neovascularization and survival of human endometriotic lesions in a mouse model.
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.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Diane S
DS
Nakamura
Andrew K
AK
Edwards
Sophia
S
Virani
Richard
R
Thomas
Chandrakant
C
Tayade
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004715:Endometriosis / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D004717:Endometrium / Q000473:pathology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D057786:Peptidomimetics / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019700:Thrombospondin 1 / Q000494:pharmacology / Q000627:therapeutic use*; D014463:Ultrasonography
D016207:Cytokines; D009842:Oligopeptides; D057786:Peptidomimetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019700:Thrombospondin 1; C554676:acetyl-glycyl-valyl-allo-isoleucyl-seryl-glutaminyl-isoleucyl-arginyl-prolyl-cysteinamide