Female Sex Steroids Increase Adrenomedullin-Induced Vasodilation by Increasing the Expression of Adrenomedullin2 Receptor Components in Rat Mesenteric Artery

Based on the favorable effects of female sex steroids in vascular functions and the potent hypotensive effects of adrenomedullin (AM), we hypothesized that AM-induced vasodilation is gender dependent, and female sex steroids enhance this effect. In endothelium-intact rat mesenteric artery, AM (1 nm-0.3 microM)-induced concentration-dependent relaxation was significantly (P < 0.05) higher in females [pD2(-log EC50 of the molar concentration), 7.05 +/- 0.10; maximal relaxation response (Emax), 69.2 +/- 3.46%] than males (pD2, 6.53 +/- 0.08; Emax, 53.28 +/- 4.86%). The increased relaxation was lost when the females were ovariectomized (OVX) (pD2, 6.14 +/- 0.24; Emax, 39.68 +/- 5.68%). The reduced relaxation response in OVX rats was reversed by administration of either progesterone (P4; pD2, 7.18 +/- 0.07; Emax, 72.4 +/- 2.76%) or 17beta-estradiol (E2; pD2, 7.00 +/- 0.14; Emax, 70.4 +/- 4.79%). AM mediates its effects through either AM(22-52)-sensitive AM1 receptors [composed of calcitonin receptor-like receptors (CLs) and receptor activity-modifying protein (RAMP)2] or AM2 receptors (CL/RAMP3), which can be antagonized more potently by calcitonin gene-related peptide(8-37) than AM(22-52). Pharmacological characterization suggested the involvement of AM2 receptors in the increased vasodilatory effect of AM in both P4- and E2-treated animals as calcitonin gene-related peptide(8-37) (10 microM) was more potent in antagonizing the AM effects (Emax, P(4): 25.92 +/- 5.32%; E2: 29.11 +/- 7.41%) than AM(22-52) (100 microM). RT-PCR studies also supported the involvement of AM2 receptors because expression of mRNA levels encoding CL (previously reported) and RAMP3 were increased in P4- or E2-treated OVX rats. In conclusion, AM-induced vasodilation is gender-dependent and increased by female sex steroids by increased expression of AM2 receptor components.