Proangiogenetic molecules, hypoxia-inducible factor-1α and nitric oxide synthase isoforms in ovarian endometriotic cysts

Abstract

Endometriosis is a common disease characterised by ectopic growth of endometrial tissue outside the uterine cavity. Angiogenesis has been implicated in the pathogenesis of the disease; some molecules, like hypoxia-inducible factor-1alpha (HIF-1alpha) and neuronal, endothelial and inducible nitric oxide synthase isoforms (nNOS, eNOS and iNOS), are known as proangiogenetic factors. We evaluated expression of these molecules by immunohistochemistry in 32 cases of ovarian endometriomas, formalin-fixed and paraffin-embedded. Analysis was focused on the cells composing the inner layer of the cyst, constituted by the ectopic endometrial glands, stromal cells and vessels, and the outer one, constituted by a fibrous layer of fibroblasts and vessels. We found that epithelial glands and capsular vessel endothelial cells showed a correlated expression of NOS isoforms; that expression of nNOS, iNOS and HIF-1alpha was correlated in epithelial glands and capsular fibroblasts; that vessel endothelial cells showed a higher mean expression for all the proangiogenetic molecules in the outer layer than in the inner one; and that capsular fibroblasts showed a higher mean expression for HIF-1alpha, iNOS and eNOS compared to the specialised stromal cells of the inner layer. Our data seem to indicate that angiogenesis is stimulated more in the outer capsule than in the inner layer of ovarian endometriotic cysts. The knowledge of the complex mechanisms associated to angiogenesis might be useful in a therapeutic approach of ovarian endometriosis based on anti-angiogenetic drugs. The therapeutic target would be mainly the capsular vasculature, more than the vasculature of ectopic endometrial tissues.

Endometriosis, a disease of the macrophage

“…Interestingly, endometrial fragments from women in which a transient ischemia had been induced by repeated clamping/declamping of the uterine artery transplanted onto the chick embryo chorioallantoic membrane demonstrated higher VEGF expression and better survival: this mechanism could facilitate implantation/establishment of endometrium at ectopic sites (Ren et al, 2011). Moreover, response to ischemia is likely to play a role in established lesions of endometriotic patients: the relative expression of HIF1α and VEGF differ at various sites within endometriotic lesions, possibly accounting for some of their heterogeneous histological characteristics (Goteri et al, 2004, 2010). …”

Hypoxia induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human endometrial cells

“…The expression of hypoxia-inducible factor (HIF)-1a is also detected during these phases in normal endometrium. The intensity of HIF-1a protein expression increases over the course of the secretory phase and is maximal during menstrual phase in glandular and stromal cells in the functional layer of endometrium (Critchley et al, 2006;Goteri et al, 2010). Based on these clinical observations and the pathophysiological characteristics shown, we postulate that expression of HIF-1a in endometriotic tissues may be up-regulated and thereby plays a role in the development of endometriosis.…”

Vascularization of endometrial tissue in abdominal cavity – the most important link in the pathogenesis of endometriosis or its vulnerable spot in terms of treatment? (review of literature)

“…Экспрессия мРНК ID-1 запускается путем аутокринного воздействия мезотелиоцитов за счет секреции TGF-β1 [11,12] [35]. Запускается активная продукция фактора ингибирования миграции макрофагов (MIF), который обладает способностью активировать митотическую активность эндотелиоцитов [36]. Также ткань эндометрия начинает синтезировать большое количество изоформ синтазы оксида азота, обладающих дополнительным ангиогенным эффектом [37,38].…”