Hypoxia-inducible factor (HIF1alpha) inhibition modulates cumulus cell function and affects bovine oocyte maturation in vitro

Various metabolic and hormonal factors expressed in cumulus cells are positively correlated with the in vitro maturation (IVM) of oocytes. However, the role of hypoxia sensing both during maturation of cumulus–oocyte complexes (COCs) as well as during the resumption of meiosis remains uncertain. HIF...

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Bibliographic Details
Published in:Biology of reproduction 2021-02, Vol.104 (2), p.479-491
Main Authors: Turhan, Aslihan, Pereira, Miguel Tavares, Schuler, Gerhard, Bleul, Ulrich, Kowalewski, Mariusz P.
Format: Article
Language:English
Subjects:
bovine cumulus cells
Cattle
Communication
Embryonic development
Embryos
Gene expression
HIF1alpha
Hypoxia
in vitro maturation
Investigations
Ovaries
Ovulation
Progesterone
Reproductive health
RESEARCH ARTICLE
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Summary:Various metabolic and hormonal factors expressed in cumulus cells are positively correlated with the in vitro maturation (IVM) of oocytes. However, the role of hypoxia sensing both during maturation of cumulus–oocyte complexes (COCs) as well as during the resumption of meiosis remains uncertain. HIF1alpha plays major roles in cellular responses to hypoxia, and here we investigated its role during bovine COC maturation by assessing the expression of related genes in cumulus cells. COCs were divided into the following groups: immature (control), in vitro matured (IVM/control), or matured in the presence of a blocker of HIF1alpha activity (echinomycin, IVM/E). We found an inhibition of cumulus cell expansion in IVM/E, compared with the IVM/control. Transcript levels of several factors (n = 13) were assessed in cumulus cells. Decreased expression of HAS2, TNFAIP6, TMSB4, TMSB10, GATM, GLUT1, CX43, COX2, PTGES, and STAR was found in IVM/E (P < 0.05). Additionally, decreased protein levels were detected for STAR, HAS2, and PCNA (P < 0.05), while activated-Caspase 3 remained unaffected in IVM/E. Progesterone output decreased in IVM/E. The application of PX-478, another blocker of HIF1alpha expression, yielded identical results. Negative effects of HIF1alpha suppression were further observed in the significantly decreased oocyte maturation and blastocyst rates from COCs matured with echinomycin (P < 0.05) or PX-478 (P < 0.05). These results support the importance of HIF1alpha for COC maturation and subsequent embryo development. HIF1alpha is a multidirectional factor controlling intercellular communication within COCs, steroidogenic activity, and oocyte development rates, and exerting effects on blastocyst rates. Summary Sentence HIF1alpha is functionally involved in controlling in vitro embryo production output in cattle. Suppression of its expression and/or function in cumulus cells during in vitro maturation impacts intercellular communication, steroid production and, consequently, oocyte and blastocyst rates.
ISSN:0006-3363
1529-7268
DOI:10.1093/biolre/ioaa196