Hypoxia-inducible factor inhibition affects luteal function with no effect on fertility in mice

Abstract

HIFs are transcription factors responsible for sensing low oxygen levels and, in response, inducing the transcription of numerous genes. One of the main processes stimulated by HIFs is the formation of new vessels to increase oxygen supply to the tissue. Formation of the corpus luteum strongly depends on the vasculature, and active angiogenesis occurs during luteinization. In this study, we aimed to analyze the role of HIF in the early formation of corpus luteum and its function, and in female fertility. To this aim, we superovulated mice using equine chorionic gonadotropin and human chorionic gonadotropin (hCG) and administered the HIF inhibitor acriflavine (ACF) to the mice 3 h before hCG. We found a decrease in ovarian HIF1A and VEGFA and in the vascular area in the animals treated with ACF. Moreover, we observed an increase in aberrant structures in the ovaries and in luteal cell apoptosis. Serum progesterone levels were decreased together with ovarian STAR expression. However, the animals treated with ACF during the early formation of the corpus luteum were completely fertile and no alterations were observed when the treated females were mated with fertile males. These results collectively suggest that HIF regulates gonadotropin-induced corpus luteum formation by acting on luteal blood vessel formation, luteal cell survival and progesterone synthesis. However, adequate HIF activity may not be essential to achieve and maintain pregnancy. These findings are significant to better understand the complex mechanisms of corpus luteum formation and identify potential abnormalities to allow better knowledge of ovarian physiology and pathologies in which this factor could be involved.