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Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Lisa M. Olson, Ph.D., Department of Obstetrics and Gynecology, Box 8064, Washington University School of Medicine, 4911 Barnes Hospital Plaza, St. Louis, Missouri 63110. E-mail: olson_l{at}kids.wustl.edu
Evidence supports the involvement of nitric oxide (NO) in ovulation, steroidogenesis, and atresia-related apoptosis. This study was designed to investigate the role of endothelial nitric oxide synthase (eNOS)-derived NO in ovulation, oocyte meiotic maturation, and ovarian steroidogenesis using wild-type (WT) mice and mice in which the gene for eNOS had been deleted (eNOS knock-out). We observed that mature eNOS knock-out females have significantly fewer pups born in each litter and a higher mortality rate of pups than those born to heterozygote or WT females (P < 0.05). To determine the influence of eNOS deficiency on ovarian function, immature WT and eNOS knock-out mice were superovulated by injecting PMSG (5 IU) followed by an injection of hCG (5 IU, ip) 48 h later. To determine whether murine oocytes expressed eNOS before (0 and 8 h post-hCG) and after ovulation (16 h post-hCG), we performed immunofluorescent staining. Positive specific staining for eNOS was observed on the surface of ovarian and ovulated oocytes obtained from WT mice, but not on oocytes from eNOS knock-out mice. To determine the role of eNOS-derived NO in ovulation, ovulated oocytes were counted 16 h post-hCG. eNOS knock-out females showed a significant reduction (by 63%; P < 0.0001) in ovulatory efficiency compared with WT females. The reduction in the ovulation rate in eNOS-deficient mice compared with that in WT mice was also associated with a higher concentration of estradiol (P < 0.01) without significant changes in the plasma progesterone level. eNOS deficiency impaired not only ovulation, but also oocyte meiotic maturation. Ovulated oocytes were classified as being in one of the following stages of meiosis: metaphase I, metaphase II, or showing atypical (degenerative) morphology. We observed that fewer oocytes from eNOS knock-out mice had entered metaphase II of meiosis, and a greater percentage remained in metaphase I or were atypical (P < 0.002) relative to those in WT mice. Furthermore, many oocytes that showed either a delay in meiotic maturation or abnormal morphology were undergoing cell death. Our results support a role for NO in the ovulatory process. The ovarian defects observed in the eNOS knock-out mice suggest that eNOS-derived NO is a modulator of oocyte meiotic maturation.
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