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Increased expression of hypoxia-inducible factor and altered expression of its dependent genes orchestrate the development of uterine fibroids. The pathways implicated in the development of uterine fibroids include proliferation, vessel morphogenesis, cell growth, adhesion, metabolic changes, migration, and myoblast differentiation.

Uterine fibroids are benign tumors in women and are also associated with the development of pregnancy-related pathology and infertility. A recent study reviewed the pathways of hypoxia-inducible factor (HIF) in the development of uterine fibroids. Despite being a benign tumor, uterine fibroids have a strong association with HIF. The novel insights of this review article are published in the journal Life.

Hypoxia-Inducible Factor in the Development of Uterine Fibroids

Increased HIF1-α expression has been reported in uterine fibroids. The genes implicated in this pathway influence various processes, including apoptosis, metabolism, regulation of nutrient and oxygen availability, and proliferation, all of which contribute to the pathogenesis of uterine fibroids. Proteins involved in the pathogenic processes that favor angiogenesis include angioprotein-1, vascular endothelial growth factor A, vascular endothelial growth factor receptor 1, tissue inhibitor of metalloproteinases 1, endothelial tyrosine kinase, epidermal growth factor, and plasminogen activator inhibitor 1. Nitric oxide synthases are involved in the apoptosis of uterine fibroid cells.

Genes Identified by Genome-Wide Association Studies

The genome-wide association studies (GWAS) catalog demonstrated that 174 gene variations are associated with the risk of uterine fibroids in different populations across the globe. The study further identified 72 GWAS genes that interact with HIF subunits, including HIF-3A, HIF-1A, HIF-1B, and HIF-2A. The study also identified 13 GWAS genes that had a direct interaction with the genes that encode for HIF subunits.

Future Perspectives and Limitations

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The study did not adhere to specific inclusion and exclusion criteria, nor did the study assess statistical power. Furthermore, there was a low number of studies evaluating the function of HIF protein in the development of uterine fibroids. Future studies should focus on the recognition of specific markers of expression of HIF and downstream factors implicated in uterine fibroids. The HIF pathways can also serve as potential therapeutic targets for the development of novel pharmacological tools.


Fedotova, Maria & Barysheva, Ekaterina & Bushueva, Olga. (2023). Pathways of Hypoxia-Inducible Factor (HIF) in the Orchestration of Uterine Fibroids Development. Life, 13(8), 1740. https://doi.org/10.3390/life13081740