Sympathetic hyperinnervation of the uterus in the estrogen receptor α knock-out mouse
Section snippets
Animals and tissue preparation
Experiments were conducted on 16 wild-type C57BI/6J mice and eight littermate ERαKO mice. NIH guidelines of laboratory animal care were followed and experimental protocols were approved by the University of Kansas Medical Center Animal Care and Use Committee. All efforts were made to minimize animal suffering and to reduce the number of animals used.
Wild-type cycling mice were studied in the diestrus (n=4) or estrus (n=4) phases of the estrous cycle as determined by vaginal smear. Eight other
Uterine innervation of the cycling wild-type mouse
In wild-type mice, PGP 9.5-IR fibers were most abundant in the circular smooth muscle layer and vascular zone separating the myometrial layers, and were less frequent in the longitudinal smooth muscle and endometrium (Fig. 1a, b). Nerve density, as determined by the percentage of uterine cross-sectional area apparently occupied by PGP 9.5-IR nerves, was significantly lower in estrus (3.8±0.3%) than at diestrus (7.3±0.3%; Fig. 1, Fig. 2, P=0.027). Uterine cross-sectional area in the ovarian
Variations in uterine sympathetic nerve density during the estrous cycle
The present study shows that uterine innervation of the wild-type mouse undergoes cyclical remodeling in concert with the phases of the estrous cycle. Immunostaining for PGP 9.5-IR nerves indicates that mouse uterine nerve density is lower at estrus than at diestrus. PGP 9.5 is widely distributed in essentially all neural tissues56 and is a reliable indicator of intact innervation.30 Therefore, the decrease in PGP 9.5-IR nerve density at estrus is likely to reflect an actual loss of uterine
Conclusions
The numbers of intact nerves present in the ovarian region of the uterine horn in the wild-type mouse varies as a function of estrous cycle stage, with high estrogen levels correlating with low numbers of sympathetic nerves. Mice in which ERα has been rendered non-functional by way of homologous recombination were found to have uteri of diminished size, but with a marked elevation in the number of sympathetic nerves, which was not altered by variations in plasma estrogen. These findings support
Acknowledgements
This work was supported by NIH grant NS39570 with core facilities provided by center grant HD02528 from the NICHD. We thank Dr Dennis B. Lubahn (University of Missouri Medical School) for permission to use the ERαKO transgenic mouse line derived from his laboratory, and Drs S. K. Dey and Sanjoy K. Das (University of Kansas Medical Center) for generously providing and genotyping the animals in this study.
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