Abstract-Estrogen receptor- knockout mice become hypertensive as they age, and males have a higher blood pressure than females. We hypothesized that the absence of estrogen receptor- may contribute to development of cardiovascular dysfunction by modification of adrenergic responsiveness in the peripheral vasculature. Small femoral arteries (internal diameter Ͻ200 m) were isolated from estrogen receptor- knockout and wild-type mice and mounted on a wire myograph. Concentration-response curves to phenylephrine and norepinephrine were compared and the contribution of adrenoceptor subtypes established using specific agonists and antagonists. The involvement of endothelial factors in the modulation of resting tone was also investigated and immunohistochemical analysis used to confirm the presence or absence of estrogen receptor expression. Compared with wild type, arteries from estrogen receptor- knockout male, but not female, mice demonstrated gender-specific enhancement of the response to phenylephrine (␣ 1 -adrenoceptor agonist), which was accompanied by elevated basal tension attributable to endothelial factors. Contractile responses to the mixed adrenoceptor agonist norepinephrine did not differ significantly between estrogen receptor- knockout and wild type; however, -adrenoceptor inhibition unmasked an enhanced underlying ␣ 1 -adrenoceptor responsiveness in estrogen receptor- knockout males. -adrenoceptor-mediated dilatation was also enhanced in estrogen receptor- knockout versus wild-type males. We suggest that estrogen receptor- modifies the adrenergic control of small artery tone in males but not in females. Key Words: gender Ⅲ endothelium Ⅲ estrogen Ⅲ arteries Ⅲ vasoconstriction Ⅲ adrenergic receptor agonists E ndogenous estrogens are considered to play an important role in cardiovascular homeostasis. Through occupancy of estrogen receptors (ERs) ␣ (ER␣) and  (ER), estrogens target genes that contribute to the regulation of vascular tone, the lipid profile, redox status, and vascular structure. However, the relative role of each ER subtype in cardiovascular responses to estrogens remains poorly understood. 1 ER␣ and ER are expressed in the endothelium and in vascular smooth muscle (VSM), but expression of the ER subtypes is gender and vascular bed dependent. 2,3 The explicit role of ER subtypes in the cardiovascular system, particularly in relation to regulation of vascular tone, has been difficult to assess because of the lack of specific ER subtype antagonists or agonists. The development of genetically modified animals in which one or other of the ERs is disrupted provides a useful alternative strategy for investigation. Zhu et al 4 reported that absence of ER leads to age-dependent hypertension in both genders of mice, and that blood pressure in males was higher. However, no mechanisms that could explain gender-related differences in hypertension were proposed, 4 and it is unlikely that the altered contractile function observed in the aorta of the ER knockout (ERKO) mice 4 would predisp...