Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide known to be involved in the regulation of vascular tone. Results of previous studies from our laboratory and others suggest that vascular sensitivity to CGRP is enhanced during pregnancy and that the female sex steroid hormones estradiol-17β (E₂) and progesterone (P₄) may be involved in this process. We hypothesized that CGRP receptors in the mesenteric artery are increased during pregnancy and with sex steroid hormone treatments. In the present study, we investigated whether pregnancy and female sex steroid hormones modulate the CGRP-receptors CGRP-A and CGRP-B in the mesenteric artery in the rat. The CGRP-A receptor consists of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 1 (RAMP₁); however, the CGRP-B receptor needs to be further characterized. Messenger RNA levels for CRLR and RAMP₁ were assessed by reverse transcription-polymerase chain reaction, and CGRP-B receptor proteins levels were determined by Western blot analysis. In addition, [¹²⁵I]CGRP binding was measured by Scatchard analysis. Both mRNA for CGRP-A (CRLR and RAMP₁) and the protein for CGRP-B receptors in mesenteric arteries were increased with pregnancy compared to nonpregnant, diestrous animals. A P₄ antagonist, RU-486, downregulated and P₄ upregulated these receptors in mesenteric arteries (P < 0.05) in pregnant rats. In adult ovariectomized rats, P₄ upregulated CRLR and RAMP₁ mRNA levels as well as [¹²⁵I]CGRP-binding sites. The CGRP-B-receptor protein levels were significantly (P < 0.05) elevated by P₄ and by combined E₂ and P₄ treatment. Together with earlier findings, these data suggest that increases in the expression of CGRP-A (CRLR and RAMP₁) and CGRP-B receptors in mesenteric arteries may be important in reducing vascular resistance and in vascular adaptations that occur during pregnancy; in addition, P₄ may be involved in this process.