Abnormal estrous cyclicity after disruption of endothelial and inducible nitric oxide synthase in mice

The roles of nitric oxide (NO) and nitric oxide synthase (NOS) in reproduct ion were studied by examining the estrous cycle of wild-type (WT) mice, ind ucible NOS (iNOS)-, and endothelial NOS (eNOS)-knockout mice. We observed a n average estrous cycle of 4.8 +/- 0.2 days in WT mice. While we observed n o significant influence of iNOS deficiency on cycle length, eNOS-knockout f emales showed a significantly longer estrous cycle (6.6 +/- 0.6 days; p < 0 .03) than WT females, due to an extension of diestrus (p < 0.03). There was no influence of iNOS deficiency on ovulation rate compared with that in WT females; however, eNOS-knockout mice showed a significant reduction (p < 0 .05) in ovulatory efficiency relative to WT or iNOS-knockout females. In co ntrast to WT females, in which the highest level of estradiol (E-2) was obs erved at 1500 h of proestrus, iNOS-knockout females reached a peak of E-2 a t 1830 h of proestrus. In eNOS-knockout females, the peak of E-2 occurred a t 1830 h, as in iNOS-knockout mice; however, E-2 levels were 5-fold and 3-f old higher (p < 0.05) than levels observed in WT and iNOS-knockout females, respectively. There was no effect of genotype on the plasma LH concentrati ons at proestrus. On the first day of diestrus, eNOS-knockout females showe d significantly higher plasma E-2 and progesterone levels (p < 0.05) relati ve to WT and iNOS-knockout females. The dysfunction in cyclicity, ovulation rate, ovarian morphology, and steroidogenesis in eNOS-knockout female mice strongly supports the concept that eNOS/NO plays critical roles in ovulati on and follicular development.