Sympathetic hyperinnervation of the uterus in the estrogen receptor alpha knock-out mouse

Uterine innervation undergoes cyclical remodeling in the adult virgin rat. Previous studies showed that ovariectomy Leads to increased uterine sympath etic nerve density. and this can be reduced by estrogen administration. How ever, the receptor mechanism by which estrogen modulates sympathetic innerv ation is unknown. The present study assessed the role of the estrogen recep tor a in establishing levels of uterine innervation by comparing the nerve abundance in mice with a null mutation of the estrogen receptor or with tho se of the wild-tripe cycling mouse. Immunostaining for total uterine innerv ation using antibodies against the pan-neuronal marker protein gene product 9.5 showed that nerve numbers in normally cycling wild-type mice were high in diestrus when circulating estrogen is at its nadir, and low at estrus, coincident with high plasma estrogen. Uteri of the estrogen receptor a knoc k-out mice were smaller than those of wild-type mice, but even when correct ed for differences in size, total innervation was 188% and 355% greater tha n that of wild-type mice at diestrus and estrus, respectively. This hyperin nervation is associated with increased numbers of nerves immunoreactive for the noradrenergic enzyme dopamine beta -hydroxylase, without obvious diffe rences in those containing calcitonin gene-related peptide or the vesicular acetylcholine transporter. While estrogen supplementation of the ovariecto mized wild-type mice significantly reduced total uterine innervation, neith er ovariectomy nor estrogen supplementation affected uterine nerve density in estrogen receptor or knock-out mice. We conclude that estrogen acting through the estrogen receptor a determines the number of sympathetic nerve terminal branches within uterine smooth mu scle target. In mice with low circulating estrogen, or high estrogen but la cking the functional estrogen receptor alpha, the uterus contains abundant sympathetic nerves, whereas estrogen acts via the estrogen receptor a to re gulate uterine innervation by reducing numbers of intact sympathetic nerves . Although it is not known whether estrogen acts on the target or neuron to initiate these changes, the estrogen receptor or apparently plays a major role in the cyclical modulation of uterine sympathetic innervation. (C) 200 1 IBRO. Published by Elsevier Science Ltd. All rights reserved.