Transcriptomic responses to hypoxia in endometrial and decidual stromal cells

Abstract

Human reproductive success depends on a properly decidualized uterine endometrium that allows implantation and the formation of the placenta. At the core of the decidualization process are endometrial stromal fibroblasts (ESF) that differentiate to decidual stromal cells (DSC). As variations in oxygen levels are functionally relevant in endometrium both upon menstruation and during placentation, we assessed the transcriptomic responses to hypoxia in ESF and DSC. In both cell types, hypoxia-upregulated genes in classical hypoxia pathways such as glycolysis and the epithelial mesenchymal transition. In DSC, hypoxia restored an ESF-like transcriptional state for a subset of transcription factors that are known targets of the progesterone receptor, suggesting that hypoxia partially interferes with progesterone signaling. In both cell types, hypoxia modified transcription of several inflammatory transcription factors that are known regulators of decidualization, including decreased transcription of STATs and increased transcription of CEBPs. We observed that hypoxia-upregulated genes in ESF and DSC had a significant overlap with genes previously detected to be upregulated in endometriotic stromal cells. Promoter analysis of the genes in this overlap suggested the hypoxia-upregulated Jun/Fos and CEBP transcription factors as potential drivers of endometriosis-associated transcription. Using immunohistochemistry, we observed increased expression of JUND and CEBPD in endometriosis lesions compared to healthy endometria. Overall, the findings suggest that hypoxic stress establishes distinct transcriptional states in ESF and DSC and that hypoxia influences the expression of genes that contribute to the core gene regulation of endometriotic stromal cells.

Nonhormonal therapy for endometriosis based on energy metabolism regulation

“…Endometrial fibroblasts are decidualized during pregnancy, allowing placenta formation and embryo implantation ( Rytkönen et al 2020 ). Placental tissue may have evolved mechanisms to tolerate hypoxic environments by expressing hypoxia-related genes such as hypoxia-inducible factor-1alpha (HIF-1α), vascular endothelial growth factor (VEGF), and transforming growth factor-beta1 (TGF-β1; Duzyj et al 2018 ).…”

“…The complex gene regulatory networks driven by the interplay between a hypoxic microenvironment and endometriotic cells allow endometriotic cells to survive (Wu et al, 2019). The effects induced by hypoxia are orchestrated by HIFs that regulate the expression of numerous genes, including VEGF, TGF-β1, PI3K/AKT, Wnt/β-catenin, and Notch (Laschke and Menger, 2012;Wilson, 2018;Rytkönen et al, 2020). Genes related to classical hypoxia pathways (e.g., HIF-1α, VEGF, and TGF-β1) have been extensively studied in endometriotic cells (Laschke and Menger, 2012;Rytkönen et al, 2020) and adjacent peritoneal mesothelial cells (Wilson, 2018).…”

“…The effects induced by hypoxia are orchestrated by HIFs that regulate the expression of numerous genes, including VEGF, TGF-β1, PI3K/AKT, Wnt/β-catenin, and Notch (Laschke and Menger, 2012;Wilson, 2018;Rytkönen et al, 2020). Genes related to classical hypoxia pathways (e.g., HIF-1α, VEGF, and TGF-β1) have been extensively studied in endometriotic cells (Laschke and Menger, 2012;Rytkönen et al, 2020) and adjacent peritoneal mesothelial cells (Wilson, 2018). A hypoxic microenvironment stimulates endometriotic stromal cells (Dai et al, 2019) and peritoneal mesothelial cells (Lin et al, 2018) to produce and stabilize HIF-1α and promote the activation of TGF-β1/Smad and VEGF signal transduction pathways, contributing to increased cellular invasiveness, adhesiveness, cell survival, EMT, MMT, adhesion and fibrosis formation, and reduced apoptotic potential (Kasvandik et al, 2016).…”

Water-Extracted Prunella vulgaris Alleviates Endometriosis by Reducing Aerobic Glycolysis

“…Recently, a cancer-like glycolytic phenotype was reported in patients with endometriosis, as measured by metabolite and transcript levels ( Marianna et al, 2017 ; Rytkonen et al, 2020 ; Zheng et al, 2021 ). Glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and pyruvate dehydrogenase kinase 1 (PDK1) have been suggested as key enzymes for maintaining glycolytic metabolism in endometriosis ( McKinnon et al, 2014 ; Young et al, 2014 ; Lee et al, 2018 ; Kido et al, 2020 ).…”

Role of CD146 (MCAM) in Physiological and Pathological Angiogenesis—Contribution of New Antibodies for Therapy

“…In atherosclerosis, a process in which vessels are progressively clogged, as plaques enlarge in size, vessel's intima thickens and oxygen supply from the arterial lumen to this area declines [72]. This creates a hypoxic state, a phenomenon that activates CD146 gene expression in addition to other inflammatory cytokines [73,74]. The newly induced inflammatory microenvironment potentiates the release of angiogenic factors that stimulate sprouting angiogenesis from the vasa vasorum [72].…”