Unmasking hypoxia's double-edged sword: Mechanistic insights into granulosa cell adaptation and dysfunction

Granulosa cells are an important component of the ovary, surrounding the oocytes. The structural characteristics of ovarian follicles limit blood perfusion, thereby naturally forming an endogenous hypoxic microenvironment within the granulosa cell - oocyte complex. External hypoxic exposure (such as in high-altitude environments) further exacerbates the hypoxic condition of the ovary, making the regulation of low oxygen on the biological functions of granulosa cells a growing focus in reproductive biology and reproductive toxicology research. In this review, we systematically summarize and analyze the various impacts of hypoxia on the core physiological processes of granulosa cells (including proliferation, apoptosis, luteinization, and steroidogenesis), emphasizing the typical molecular signaling pathways that mediate these hypoxia-induced effects. We note that hypoxia is a double-edged sword in ovarian physiology: it regulates the adaptive physiological responses of granulosa cells to support normal follicle development, but excessive or persistent hypoxia can cause granulosa cell dysfunction and damage the development of ovarian follicles. Analyzing the exact hypoxia-mediated regulatory mechanisms in granulosa cells not only deepens our understanding of ovarian physiological homeostasis but also provides new insights into the mechanisms of hypoxia-related ovarian reproductive diseases.