Vascular endothelial growth factor (VEGF) is a potent modulator of vascular remodeling and angiogenesis in the uterus. Recently, neuropilins (Npn), semaphorin receptors associated with neuronal guidance, were demonstrated to bind VEGF isoforms with high affinity, facilitating VEGF(165) binding to the tyrosine kinase receptor VEGFR2. The current studies examined rat uterus neuropilin expression and regulation. Npn-1 and Npn-2 transcripts and 135-kDa proteins were observed in uterine extracts. Both uterine vascular endothelial cells and glandular epithelium expressed Npn-1 immunoreactivity, whereas Npn-2 was restricted to the glandular epithelium. In hormone-replaced ovariectomized animals, progesterone increased uterine 6.5-kb Npn-1 messenger RNA (mRNA) expression approximately 2-fold compared with that in tissues from ovariectomized controls. 17ss-Estradiol alone had no effect, but blunted the progesterone response; by contrast, Npn-2 mRNA expression was decreased by estrogen. VEGFR2 mRNA was coregulated with Npn-1. Consistent with these results, Npn-1 mRNA expression was augmented nearly 7- and 4-fold at metestrus and diestrus, respectively, during periods of high progesterone; Npn-2 mRNA expression was not significantly altered during the estrous cycle. The regulated expression and differential localization of neuropilins in the rat uterus suggest that these receptors may participate in hormonally regulated changes occurring throughout the female reproductive cycle.