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

Nakamura, Diane S.; Edwards, Andrew K.; Virani, Sophia; Thomas, Richard; Tayade, Chandrakant

doi:10.1016/j.ajpath.2012.05.010

Cited by 10 publications

(18 citation statements)

References 47 publications

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“…Prior to the study, to confirm that each lot of the thrombospondin-1 mimetic peptide ABT-898 had anti-angiogenic properties, we performed in vitro angiogenesis assays as previously described [13]. ABT-898 was able to completely ameliorate endothelial cell tube formation in vitro (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…ABT-898 was able to completely ameliorate endothelial cell tube formation in vitro (data not shown). Non-pregnant cycling female mice were treated for 21 consecutive days with ABT-898 at a concentration (100 mg/kg) that had previously been shown to reduce neovascularization of endometriosis lesions [13], or 5 % dextrose control. Vaginal cytology was analyzed each day to assess the effect of ABT-898 on the estrous cycle.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that female mice treated with ABT-898 prior to pregnancy had normal litters and placental structures [13]. Here we wanted to establish what effect ABT-898 would have on pregnancy if it was injected chronically over the course of mouse gestation.…”

Section: Resultsmentioning

confidence: 99%

“…Peripheral blood plasma was collected as previously described [13] prior to treatment, during the second week of treatment with ABT-898 or 5 % dextrose control, and on the last day of treatment. 15 μL of plasma per sample was used in the assay.…”

Section: Methodsmentioning

confidence: 99%

“…It also binds and sequesters vascular endothelial growth factor (VEGF), the primary pro-angiogenic growth factor, limiting its bioavailability [11, 12]. 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. Mice that had previously been treated with ABT-898 were able to become pregnant, had normal decidual and placental morphology, and litter sizes indicating no lasting effects of ABT-898 on female reproduction.…”

Section: Introductionmentioning

confidence: 99%

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Chronic effects of an anti-angiogenic thrombospondin-1 mimetic peptide, ABT-898, on female mouse reproductive outcomes

Edwards

Olariu

Nakamura

et al. 2016

Reprod Biol Endocrinol

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Chronic effects of an anti-angiogenic thrombospondin-1 mimetic peptide, ABT-898, on female mouse reproductive outcomes

Edwards

Olariu

Nakamura

et al. 2016

Reprod Biol Endocrinol

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Non‐hormonal targets underlying endometriosis: A focus on molecular mechanisms

Che

Chen

et al. 2015

Molecular Reproduction Devel

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Endometriosis is regarded as a hormone-dependent disease. Current therapeutic approaches to treating this common gynecological disorder mainly depend on surgical and hormonal interventions, but the high rate of disease recurrence as well as the side effects related to such therapies make it difficult for patients to recover completely. Molecular evidence has recently suggested that the source of endometriosis can be both hormone-dependent and influenced by the dysregulation of some signaling cascades. In this review, we focus on the non-hormonal triggers of endometriosis and the pre-clinical compounds designed to correct these signaling defects in order to achieve a better understanding of the disease as well as novel approaches to treating it.

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The Role of the Microenvironment in Endometriosis: Parallels and Distinctions to Cancer

Rogers

2022

Biomarkers of the Tumor Microenvironment

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

Cited by 10 publications

References 47 publications

Chronic effects of an anti-angiogenic thrombospondin-1 mimetic peptide, ABT-898, on female mouse reproductive outcomes

Chronic effects of an anti-angiogenic thrombospondin-1 mimetic peptide, ABT-898, on female mouse reproductive outcomes

Non‐hormonal targets underlying endometriosis: A focus on molecular mechanisms

The Role of the Microenvironment in Endometriosis: Parallels and Distinctions to Cancer

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