Peptide inhibitors of angiogenesis in endometriosis and the female reproductive system
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Endometriosis, characterized by the growth of endometrium outside the uterine cavity, is a disease which causes pelvic pain, inflammation and associated with infertility. Endometrium, which exits the uterus through retrograde menstruation, must establish a new blood supply as it attaches and invades into ectopic tissues to form an endometriosis lesion. Angiogenesis is therefore essential in endometriosis disease progression. The inhibition of blood vessel growth by anti-angiogenic agents is a potential strategy to manage endometriosis disease progression. This thesis investigated angiogenesis of endometriosis lesions, and evaluated a novel anti-angiogenic peptide as a potential therapeutic to manage endometriosis. An atlas on the microscopic anatomy of the pregnant mouse uterus is also presented. Synuclein-γ (SNCG), a protein involved in cellular proliferation, was found to have elevated expression in endothelial cells of endometriosis tissue compared to eutopic endometrium. In an alymphoid xenograft mouse model of human endometriosis, where human endometrium is engrafted into the peritoneal cavity of Rag2-/-/IL2r-/- female mice, peptide inhibition of SNCG resulted in reduced vascularization of endometriotic lesions. This study indicates that SNCG has a potential role in angiogenesis of endometriosis lesions. Using the same alymphoid mouse model, we evaluated the effect of an anti-angiogenic thrombospondin-1 mimetic peptide, ABT-898, on angiogenesis of endometriotic lesions. ABT-898 inhibited endothelial cell proliferation and tube formation in vitro. Mice treated with ABT-898 showed reduced vascularity of endometriosis lesions compared with control. Angiogenesis is also an essential process in the female reproductive system. Females with endometriosis are of reproductive age, so it is essential to establish that anti-angiogenic therapies do not iii interfere with reproduction. We evaluated the effect of ABT-898 on angiogenesis in the female reproductive tract in non-pregnant mice. ABT-898 did not affect estrous cyclicity, or vascularity of the uterus or ovary in non-pregnant animals. ABT-898 did not alter litter size or pup weight when given to pregnant mice throughout gestation. In summary this thesis implicated a role for SNCG in angiogenesis of endometriosis lesions, and found that ABT-898 could be a useful therapeutic to manage endometriosis disease progression as it reduces angiogenesis of endometriotic lesions, while having no observable effect in reproductive organs.