HYPOXIA AND REPRODUCTIVE HEALTH: Hypoxia and ovarian function: follicle development, ovulation, oocyte maturation

Abstract

The ovarian follicle provides the oocyte with the ideal environment for growth and development in preparation for ovulation and fertilisation. The follicle undergoes many structural changes as it grows, including changes in vasculature, cell proliferation and differentiation and the formation of a follicular fluid-filled antrum. These changes collectively create a low oxygen environment within the follicle. Thus, the oocyte itself develops in a potentially hypoxic environment. The survival of hypoxic tissues is controlled by hypoxia-inducible factors (HIFs) that are activated in a low oxygen state. The understanding of HIF pathways is growing across all fields of biology, and its role in ovarian development is steadily gaining clarity. One of the genes upregulated by HIF is vascular endothelial growth factor, the main inducer of angiogenesis which is required for follicle development and luteal formation. Ovulation is also intrinsically linked to HIF activity through the ovulatory luteinizing hormone surge increasing HIF expression. The role for HIF in oocyte maturation is less understood, as efforts to replicate the low oxygen environment of the in vivo follicle are not achievable by culturing in low oxygen alone. There is potential for other factors present in vivo, but lost in vitro, to be involved in oxygen regulation. One factor of interest is haemoglobin, the oxygen-binding protein, which brings the exciting possibility of sensitive oxygen regulation, consequently affecting HIF-regulated gene expression. A thorough understanding of oxygen regulation within the follicle would provide vital applications for the field of assisted reproductive technologies, in particular in vitro oocyte maturation.

Endothelin 2: a key player in ovulation and fertility

“…In support of this hypothesis, the promoter region of the Edn2 gene contains a hypoxia response element, and GCs of preovulatory follicles experience hypoxia as the follicle rapidly grows after the LH surge, without an accompanying increase in oxygen from blood vessels located outside of the follicle (Klipper et al 2010). Of note, the antrum of a growing follicle is not vascularized, causing the follicle to experience hypoxia as it experiences rapid growth in a short time (Suzuki et al 1998, Zhang et al 2019, Lim et al 2021, Tang et al 2021.…”

Redox Regulation and Oxidative Stress in Mammalian Oocytes and Embryos Developed In Vivo and In Vitro

“…Oocyte maturation, fertilisation and embryo development in the reproductive system take place in a highly complex milieu of factors from the mother and the oocyte/embryo itself. During folliculogenesis there is a steady decline in O 2 tension in the follicular fluid [62,63] and around the time of ovulation there is a decrease in blood flow to the ovary, thus subjecting the oocyte to decreasing O 2 tension from the primary follicle stage to the point of ovulation [62][63][64]. There is also a decrease in O 2 tension from the top of the oviduct (~8%), where fertilisation takes place, to the uterus (~2%), at the time of blastocyst formation and implantation [63,65] (Figure 3).…”

Orphan nuclear receptors in angiogenesis and follicular development

“…In addition, mRNA for soluble VEGFR2 was found in greater abundance in atretic bovine follicles compared to healthy follicles (Zamora-Gutiérrez et al 2019). Additionally, antral follicle growth is characterized by a reduction in the oxygen levels within the follicle in several species, including human and cow (Lim et al 2021), and it is well known that hypoxia is necessary for normal granulosa cell function (Zeebaree et al 2018). Recently, a reduction in the mRNA of soluble VEGFR1 and soluble VEGFR2 in bovine granulosa cells cultured under hypoxic conditions has been demonstrated (Hernández-Morales et al 2021), suggesting that hypoxia may promote angiogenesis by reducing the abundance of soluble VEGFRs.…”