Obesity disrupts ovarian hemodynamics during the preovulatory and luteal phases in mice†

Ovulation failure accounts for >25% of infertility cases in reproductive-age women in the United States, with obese women three times more likely to experience anovulatory infertility. The mechanisms by which obesity impairs ovulation remain unclear. The preovulatory luteinizing hormone (LH) surge induces changes in ovarian vasculature crucial for ovulation. We hypothesized that obesity disrupts ovarian vascular function, contributing to impaired ovulation. Using Doppler ultrasonography, we assessed ovarian hemodynamics in adult normal-weight mice and two obese groups: high-fat diet (HFD) and Agouti viable Yellow (AvY) mice. Both obese groups had reduced ovulation rates following superovulation. In normal-weight mice, flow velocity in the ovarian vessels increases within the first hour following ovulation induction by human chorionic gonadotropin, whereas this increase was absent in obese mice. This change in velocity correlated with ovulation rates, suggesting its importance for ovulation success. Ovarian hemodynamics were disturbed in naturally cycling obese mice compared to normal-weight controls during diestrus. Immediately before ovulation induction, ovarian vasculature analysis through lectin labeling revealed an increased abundance of capillaries in HFD ovaries compared to AvY; transcriptomic analysis of granulosa cells and ovarian stroma identified differentially expressed genes involved in vascular development, extracellular matrix organization, and inflammation, all crucial for vascular function and ovulation. This study characterizes for the first time in vivo ovarian hemodynamics in normal-weight adult mice, and demonstrates disrupted ovarian hemodynamics in obese mice during the preovulatory and luteal phases. These findings pinpoint that improving ovarian vascular function could be a therapeutic target for enhancing ovulation in obese women.