Hypoxia Induces Hypoxia-Inducible Factor 1α and Potential HIF-Responsive Gene Expression in Uterine Leiomyoma

Uterine leiomyoma is characterized by abundant extracellular matrix and broad avascular areas, both constantly resulting in hypoxia, suggesting some hypoxia-induced response function. Here, we examined whether hypoxia-inducible factor 1 alpha (HIF-1 alpha)- mediated hypoxic response function in uterine leiomyoma. Immunoblotting detected higher basal HIF-1 alpha protein expression in nuclear extracts from uterine leiomyoma tissues than in those from the adjacent myometrium (P = .0011). Immunohistochemical analysis revealed the presence of HIF-1 alpha-positive cellular components in both leiomyoma and surrounding myometrial tissues. Hypoxia decreased HIF-1 alpha messenger RNA (mRNA), but increased HIF-1 alpha protein in primary culture leiomyoma smooth muscle cells, and caused translocation of HIF-1 alpha from the cytoplasm to the nucleus. Hypoxia upregulated mRNAs of 6 potential HIF-responsive genes (ALDOA, ENO1, LDHA, VEGFA, PFKFB3, and SLC2A1). Chromatin immunoprecipitation quantitative polymerase chain reaction revealed that hypoxia significantly increased recruitment of HIF-1 alpha binding to putative HIF-responsive elements in the HIF-responsive genes, suggesting that the HIF transcriptional complex initiates hypoxia-induced transcription of HIF-responsive genes. These results demonstrated a HIF-1 alpha-mediated hypoxic response in uterine leiomyoma.