Antiangiogenesis Therapy for Endometriosis

Abstract

It is known that angiogenesis is of pivotal importance for the development of endometriosis. However, in the treatment of endometriosis patients, prevention of endometriosis lesion development only will not be sufficient as a therapy. Treatment options, aimed at interfering with established lesions, have to be developed. In this study we evaluated whether inhibition of angiogenesis by angiostatic therapy is also effective in antagonizing the sustentation of endometriosis. We evaluated the effect of the angiostatic compounds antihuman vascular endothelial growth factor, TNP-470, endostatin, and anginex on the growth of established endometriosis lesions in the nude mouse model. We show that human endometrium in the proliferative endometrium is highly angiogenic and that vascular endothelial growth factor-A is the most important angiogenesis promotory factor. The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions. In the remaining lesions, the number of pericyte-protected vessels is not different in control and treated mice; however, the number of unprotected vessels was significantly reduced in the groups treated with the angiostatic agents. Our data demonstrate that inhibitors of angiogenesis effectively interfere with the maintenance and growth of endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis.

The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse model of endometriosis

“…In this context, previous work by our group (Ferrero et al 2010) and other authors (Cristina et al 2005) has shown that cell populations expressing DRD2 (granulosa or pituitary cells) inhibit the secretion of VEGF in either an autocrine or a paracrine fashion. In this regard, it is known that most immune cell subtypes express DRD2 (McKenna et al 2002), and among them, macrophages are known to express large amounts of VEGF (Nap et al 2004). Moreover, the ability of macrophages to reduce angiogenesis when activated by dopamine has recently been described (Chakroborty et al 2008).…”

“…The growth of newly formed blood vessels is of pivotal importance in the development of endometriosis (Nap et al 2004). Angiogenesis involves complex molecular interactions between endometrial tissue, peritoneal tissue, infiltrating leucocytes, and fibroblasts (Hull et al 2008).…”

“…Numerous peritoneal blood vessels surround active endometriotic lesions, and the implant itself is also endowed with a rich vascularized area; this can be observed under histological examination (Nisolle et al 1993, Nap et al 2004 and confirms the essential role that angiogenesis plays in the development and continuation of endometriotic lesions (Shifren et al 1996, Donnez et al 1998, Becker et al 2005. In this regard, it has been observed that human endometrium engrafted in immunocompromised mice promotes the growth of neovessels from the surrounding host vascular network in order to provide the endometriotic lesions with an adequate blood supply.…”

“…In this regard, it has been observed that human endometrium engrafted in immunocompromised mice promotes the growth of neovessels from the surrounding host vascular network in order to provide the endometriotic lesions with an adequate blood supply. Vascular endothelial growth factor (VEGF) acts through its VEGFR2 to play a pivotal role in the control of angiogenesis (McLaren et al 1996) and so several antiangiogenic agents that target this pathway have been successfully used to disrupt the vascular supply of heterologous implants in inmmunodeficient animal models of endometriosis (Nap et al 2004). However, the commercial anti-VEGF/VEGFR2 used in such experiments can induce severe side effects (Eremina et al 2008), which rules out its use in the treatment of endometriosis in young and otherwise healthy women.…”

Innervation of ectopic endometrium in a rat model of endometriosis

“…It is therefore possible that if at least some growths in women become innervated, then variations in the characteristics of this innervation, such as the type and density of afferent fibers, may be the more important variable. Such afferent and efferent innervation could also contribute to maintenance of the growths, and thus, like emerging treatments aimed at reducing vascularization of ectopic endometrial growths (47,48), represent additional new avenues for treatment.…”