| Objective: To investigate the effects of different kinds of inhibitors of angiogenesison the growth and angiogenesis of established endometriosis lesions and to study the feasibility of antiangiogenesis therapy for endometriosis.Methods: 1. Eutopic endometrium of women with endometriosis was transplanted to the non-vascular region of the chick embryo chorioallantocic membrane (CAM) on 8-day-old chicken embryo, and the chicken embryo randomized into inoculation group, inoculation treatment groups and blank groups. The inoculation treatment groups administered angiostatic angents: recombinant human endostatin YH-16 (5ug/20ul/d), thalidomide (10ug/20ul/d), integrin avβ3 monoclonal antibody LM609 (10ug/20ul/d), and vascular endothelial growth factor (VEGF) monoclonal antibody (10ug/20ul/d), whereas the inoculation group received equivalent volume sterile PBS as control. Seventy-two hours after transplantation of the endometrium fragment onto the CAM, we examined the effects of angiostatic angents on the vascularization and on endometriosis-like lesion formation in the CAM model through color micrographs, Calculation of vascularization index and histological evaluation. 2. Eutopic endometrium of women with endometriosis was transplanted to the severe combined immunodeficiency disease (SCID) mice, and the mice randomized into treatment groups and control group. Two weeks after implantation of endometrium fragment, the treatment groups were injected into the peritoneal cavity with recombinant human endostatin YH-16 (2mg.kg-1.d-1), thalidomide (50mg.kg-1·d-1), integrin avβ3 monoclonal antibody LM609 (250ug.twice.w-1), and VEGF monoclonal antibody (Smg-kg-1.d-1). The control group was given equivalent volume sterile PBS (200ul.d-1). The volumes of endometriotic lesions in SCID mice were measured every three days, and all the treatment lasted 14 days. Weused immunohistochemistry to determine microvessel density (MVD) and expression of VEGF to value the treating effect.Results: 1. Transplantation of endometrium onto the CAM led to a strong angiogenic response in the chicken tissue; the number of newly formed vessels were more significantly increase in inoculation group than in blank group (P<0.01). There was a statistically significant decrease on vascularization of the groups using angiostatic agents compared with inoculation group (P<0.01). Endometriosis-like lesion formation was significantly impaired after treatment with angiostatic agents, which was associated with decreased vessel densities in the surrounding chorioallantoic membrane and optical microscopy showed more necrosis in the endometriosis-like lesions. 2. The SCID mouse model of endometriosis with subcutaneous inoculation can provide high survival rate of implantation, convenient observation, more visual information on the growth and response of these implants to environmental manipulation. Angiostatic angents inhibited the growth of endometriotic lesions in mice. The differences were statistically significant for the quality and volume of endometriotic lesion after treatment in YH-16 or LM609 or VEGF monoclonal antibody compared with the control group (P<0.05). Microscopic examination showed the bulk of the endometrial tissue decreased and glands depauperated. The glandular epithelium had partially degenerated, and necrotic debris was presented in the endometrial stroma. MVD was decreased significantly in the groups using angiostatic angents compared with the control group (P<0.05). The expression levels of VEGF statistically significantly reduced in lesions from mice treated with endostain YH-16 and VEGF monoclonal antibody compared with controls (P<0.05).Conclusion: 1. Establishment of a new blood supply is essential or critical for the survival and development of endometrium in an ectopic location, and the endometriotic lesions are larger in areas with a rich blood supply, and activation of angiogenesis might be a key factor in the pathogenesis of endometriosis. 2. The inhibitors of angiogenesis effectively interfere with the maintenance and growthof endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis. |
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