Hypoxia Promotes Ectopic Adhesion Ability of Endometrial Stromal Cells via TGF-β1/Smad Signaling in Endometriosis

Abstract

Hypoxia plays a vital role in the progression of endometriosis. Additionally, integrin-mediated aberrant adhesion is also essential for establishment of endometriotic lesions. In this study, we sought to determine the function of hypoxia in integrin-mediated adhesion of endometrial stromal cells (ESCs) in endometriosis. The expressions of adhesion molecule integrins (integrin α5, integrin αV, integrin β3, and integrin β5) were determined in 15 normal endometria and 15 paired eutopic and ectopic endometria by immunohistochemistry. Thirteen primary ESCs from patients with peritoneal endometriosis in the proliferative phase were cultured under a hypoxic (1% O2) or normoxic (21% O2) environment, and the expression levels of hypoxia-inducible factor (HIF)-1α, transforming growth factor (TGF)-β1, and integrins were detected by quantitative reverse transcription polymerase chain reaction and western blot. The alteration of integrins in endometriotic mouse models were also explored. Our results demonstrated that HIF-1α and integrins were highly expressed in ESCs of endometriotic lesions compared with ESCs of eutopic and normal endometrium. Hypoxia treatment significantly increased ESC adhesion abilities and integrin expression, which were positively correlated with TGF-β1 expression. Both TGF-β1 and hypoxia enhanced ESC adhesion properties, whereas hypoxia combined with TGF-β1 receptor inhibitor inhibited ESC adhesion. Knockdown of HIF-1α attenuated TGF-β1/Smad signaling activation and integrin expression and reduced ESC adhesion. Higher expression levels of HIF-1α, TGF-β1, and integrins were detected in endometriotic cysts from mice models. Our findings provide a novel insight of endometriosis that the hypoxic microenvironment stimulates ESCs to produce excessive TGF-β1 and activates the TGF-β1/Smad signaling pathway, thus enhancing integrin expression and the adhesion ability of ESCs.

A novel silkworm pupae carboxymethyl chitosan inhibits mouse L929 fibroblast proliferation

“…The activated Smad2/3 proteins with Smad4 proteins form oligomeric complexes and translocate into nucleus, where they induce the expression of target genes, contributing to the development fibrosis [25]. Studies in vitro and in vivo have revealed TGF-β 1 /Smad signaling to be a significant mediator of fibrosis in many diseases such as renal fibrosis in diabetic nephropathy [6,[26][27][28] and endometriosis [29]. Previous study found that the expression of TGF-β 1 protein is upregulated in a rat cecal abrasion model, and treatment with SPcarboxymethyl chitosan suppresses TGF-β 1 expression [17].…”

Pathophysiological implications of hypoxia in human diseases

“…Two challenges that the retrograded cells have to face are hypoxic stress and adhesive ability. Recently, two studies reported that hypoxia enhances cell adhesive ability of the endometrial stromal cells by inducing the expression of cell adhesion molecules such as integrin α5, αV, β3, and β5 via TGF-β1/Smad signaling and anthrax toxin receptor 2 (ANTXR2) via HIF-1α-dependent manner [84,87]. Furthermore, hypoxia-induced ANTXR2 expression is mediated by downregulation of EZH2 causing epigenetic change in ANTXR2 locus [84].…”

The Endometriotic Tumor Microenvironment in Ovarian Cancer

“…Hypoxia is thought to be critical to the survival and invasion of endometriotic cells through multiple mechanisms including autophagy [ 65 , 66 , 67 , 68 ], TGFβ signaling [ 69 ], and signal transducer and activator of transcription 3 (STAT3) signaling [ 70 , 71 , 72 ]. In endometriosis, hypoxia stabilizes hypoxia inducible factor-1α (HIF1A) which downregulates dual-specificity phosphatase-2 (DUSP2) directly and indirectly through miR-20a [ 73 ].…”