7770 Damage of Ovarian Vasculature by Chemotherapies induces Ovarian Dysfunction in Mice

Abstract

Abstract Disclosure: W. So: None. R. Dong: None. Y. Luan: None. A. Abazarikia: None. S. Kim: None. Background: Chemotherapy demonstrates efficacy to destroying cancer cells; however, it can inadvertently impact normal healthy cells, leading to irreversible side effects, particularly affecting the ovaries in female patients. Female cancer survivors encounter endocrine dysfunction and infertility due to ovarian damage caused by gonadotoxic cancer therapies. The ovary, a vital organ responsible for producing oocytes and endocrine hormones, faces significant challenges following such treatment. A study with premenopausal breast cancer patients reported a significant reduction in ovarian blood flow and volume immediately following chemotherapy. The preservation of ovarian function depends on the ovarian vasculature in supporting the development and maintenance of ovarian follicles. Despite its importance, the relationship between ovarian vasculature and follicle following chemotherapy has not been studied. Results: To investigate the direct impacts of chemotherapy, ovaries from postnatal 5 CD-1 mice were subjected to testing with three chemotherapeutic agents: cisplatin (CDDP), cyclophosphamide (CPA), and doxorubicin (DOXO). The expression of CD31/PECAM-1 (platelet endothelial adhesion molecule) exhibited a significant decrase after 96 hours of culture with 4-HC, an active metabolite of CPA. This reduction implies that ovarian vasculature was also compromised when chemotherapy eliminated immature follicles. In order to evaluate the influence of vascular endothelial growth factor (VEGF) in safeguarding both vasculature and ovarian follicles, ovaries were co-cultured with VEGF165 or VEGF165b in combination with chemotherapy. Interestingly, pre-treatment with VEGF165 before 4-HC led to an increased expression of CD31 in the cortex area, while VEGF165b further diminished CD31 expression compared to treatment with 4-HC alone. Additionally, adolescent CD-1 mice were intraperitoneally injected with CDDP, CPA, or DOXO, and ovaries were harvested one week after injection. Ovaries treated with chemotherapeutic agents exhibited a reduction in ovary weight and decreased CD31 expression compared to control mice. Conclusions: We propose that these chemotherapeutic agents not only induced the loss of ovarian follicles but also affected ovarian vasculature in mice. This suggests a potential decrease in folliculogenesis within the ovary, coupled with the depletion of ovarian reserve, as the delivery of nutrients and oxygen to growing ovarian follicles may be compromised. VEGF165 may play a beneficial role in maintaining ovarian function by safeguarding ovarian vasculature following chemotherapy. Understanding these intricate dynamics is essential for developing strategies to mitigate the negative impact of cancer therapies on reproductive health in female cancer survivors, particularly in preserving endocrine function and reproductive lifespan. Presentation: 6/2/2024