THROMBOSPONDIN-1 ANALOG, ABT-898, INHIBITS ENDOMETRIOTIC LESION VASCULARIZATION WITHOUT AFFECTING FERTILITY OR PREGNANCY OUTCOMES IN A MURINE MODEL OF ENDOMETRIOSIS
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Endometriosis is a gynecological disease defined as the growth of endometrium outside of the uterus. Although linked to 50% of female infertility cases, current medical treatments fail to maintain fecundity. Since the survival of endometriotic lesions is dependent on their early neovascularization, antiangiogenic therapies specifically targeting blood vessel growth could be a promising therapeutic option for the treatment of endometriosis. Angiogenesis, the branching of new blood vessels from existing vasculature, promotes robust vascularization of lesions. ABT-898 (Abbott Laboratories), a thrombospondin-1 analog, induces endothelial cell apoptosis while sequestering pro-angiogenic growth factors. We postulated that ABT-898 would reduce endometriotic lesion vascularization while physiological angiogenesis and pregnancy remained unaffected in a murine model of endometriosis. The antiangiogenic effect of ABT-898 was tested in a human umbilical vein endothelial cell line revealing disruption of endothelial tube branching. Two in vivo experiments were conducted in which endometriosis was induced in female alymphoid BALB/c-Rag2-/-Il2rg-/- mice by adhering sections of human endometrium to the abdominal wall. Lesions from ABT-898 treated mice contained a reduced number of CD31+ endothelial cells and a decrease in blood flow supplying the lesion compared to 5% dextrose controls. Reproductive status was evaluated through maintenance of pregnancies up to gestation day 12 revealing unaffected implantation site structure and physiological angiogenesis. In a trans-generational study, pregnant F0 generation mice received ABT-898 or 5% dextrose injections on gestation days 7, 9, 11, 13, 15, 17, and 19. F1 generation mice were raised to reproductive age and bred resulting in litters (F2 generation) comparable in size to the F0 generation litters. Chronic exposure to ABT-898 did not affect angiogenic plasma cytokine levels in F0 generation mice. In addition, physiological angiogenesis was unaffected within the uteri of ABT-898 treated mice. Histological examination of the kidney, liver, ovary, and uterus revealed no structural abnormalities in F0 and F1 generations exposed to ABT-898. These results suggest that ABT-898 inhibits pathological angiogenesis within endometriotic lesions without affecting physiological angiogenesis involved in pregnancy and organ function across three generations of mice. Further research will establish the effects of ABT-898 on embryonic development, organ toxicity, and physiological angiogenesis in all organs.