Hypoxia and the endometrium: An indispensable role for HIF-1α as therapeutic strategies

Abstract

Hypoxia-inducible factor 1 alpha (HIF-1α) is a major molecular mediator of the hypoxic response. In the endometrium, local hypoxic conditions induced by hormonal fluctuations and endometrial vascular remodeling contribute to the production of HIF-1α, which plays an indispensable role in a series of physiological activities, such as menstruation and metamorphosis. The sensitive regulation of HIF-1α maintains the cellular viability and regenerative capacity of the endometrium against cellular stresses induced by hypoxia and excess reactive oxygen species. In contrast, abnormal HIF-1α levels exacerbate the development of various endometrial pathologies. This knowledge opens important possibilities for the development of promising HIF-1α-centered strategies to ameliorate endometrial disease. Nonetheless, additional efforts are required to elucidate the regulatory network of endometrial HIF-1α and promote the applications of HIF-1α-centered strategies in the human endometrium. Here, we summarize the role of the HIF-1α-mediated pathway in endometrial physiology and pathology, highlight the latest HIF-1α-centered strategies for treating endometrial diseases, and improve endometrial receptivity.

Keywords: Decidualization; Endometrial diseases; Endometrium; HIF-1α; Hypoxia; Menstruation.

Graphical abstract

Fig. 1

Endometrial HIF-1α fluctuates during menstruation and decidualization. During menstruation and decidualization, the expression of endometrial HIF-1α is dominated by the stimulation of local hypoxia signals and can also be regulated by essential molecules, such as progesterone, lactate, and Stathmin 1. The upregulation of the HIF-1α and its downstream factors induces the proliferation of endometrial parenchymal cells, angiogenesis, and the recruitment of immune cells, ensuring the endometrium with potent regenerative and differentiative capacities. AM, adrenomedullin; CXCR4, C-X-C motif chemokine receptor 4; dNK, decidual natural killer cell; EGLN1, egl-9 family hypoxia-inducible factor 1; GDF-15, growth differentiation factor 15; HIF-1α, hypoxia-inducible factor 1 alpha; IGF-1, insulin-like growth factor 1; IL-8, interleukin-8; LDHA, lactate dehydrogenase A; MMP2, matrix metalloproteinase 2; VEGF, vascular endothelial growth factor; YAP, yes-associated protein; α-KG, α-ketoglutarate.

Fig. 2

Essential roles of HIF-1α in the development of endometrial diseases. HIF-1α plays versatile roles in endometrial diseases. The activation of the HIF-1α pathway is potently involved in parenchymal cell proliferation and migration, inflammatory responses, and drug resistance, leading to the development of endometriosis, endometritis, intrauterine adhesion, endometrial senescence, and endometrial cancer. ADAR1, adenosine deaminase 1 acting on RNA; AGR2, anterior gradient 2; AKT, protein kinase B; ALKBH5, AlkB homolog 5; AMP, adenosine 5′-monophosphate; AMPK, Adenosine 5′-monophosphate (AMP)-activated protein kinase; ANXA2, annexin A2; COX2, cyclooxygenase2; DNMT1, DNA methyltransferase 1; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; ERRα, estrogen-related receptor alpha; FAK, focal adhesion kinase; CircFOXO3, circular RNA forkhead box O3; FSHR, follicle-stimulating hormone receptor; GPER, G protein-coupled estrogen receptor; HIF-1α, hypoxia-inducible factor 1 alpha; HMGB1, high mobility group box 1; IL-8, interleukin-8; JAK1, tyrosine-protein kinase 1, KIF23, kinesin family member 23; LDHA, lactate dehydrogenase A; oxLDL, oxidized low-density lipoprotein; MiR, microRNA; mTOR, mammalian target of rapamycin; NLRP3, NOD-like receptor thermal protein domain associated protein 3; NTRK2, neurotrophic receptor tyrosine kinase 2; PD-L1, death ligand 1; PGI₂, prostaglandin I₂; PI3K, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; SNAI2, snail family transcriptional repressor 2; SOX2, SRY-box2; VEGF, vascular endothelial growth factor.

Fig. 3

The HIF-1α pathway and potential interfering targets treating endometrial diseases. Interfering targets: a. Interfering HIF-1α gene transcription; b. Downregulating HIF-1α mRNA levels; c. Blocking HIF-1α protein translation; d. Disrupting HIF-1α protein stability; e. Influencing HIF-1α nuclear accumulation; f. Decreasing HIF-1 transcriptional activity; g. Inhibiting the interaction between HIF-1 and HRE. AKT, protein kinase B; ARE, antioxidant response element; CBP, cyclic-AMP response binding protein; CircR, Circular RNA; FIH-1, factor inhibiting HIF-1; HDAC, histone deacetylase; HIF-1α, hypoxia-inducible factor 1 alpha; HRE, hypoxia-responsive element; HSP, heat shock protein; KAT, lysine acetyltransferase; MiR, microRNA; mTOR, mammalian target of rapamycin; NRF2, nuclear factor erythroid 2-related factor 2; PHD, prolyl hydroxylase domain; PI3K, phosphatidylinositol 3-kinase; VHL, von Hippel-Lindau; 2-ME2, 2-Methoxyestradiol.