Role of Sex Differences and Effects of Endothelial NO Synthase Deficiency in Responses of Carotid Arteries to Serotonin

ABSTRACT—We examined the hypothesis that contraction of the carotid arteries to serotonin is normally inhibited by endothelial NO synthase (eNOS) and is enhanced in mice lacking the gene for eNOS. Because the influence of eNOS may vary with the sex of the mouse, we also tested whether responses to serotonin were dependent on sex. We studied carotid arteries in vitro from littermate control (eNOS) mice, heterozygous (eNOS) mice, and homozygous eNOS-deficient (eNOS) mice (male and female). Contraction to serotonin was greater in male eNOS mice than in female eNOS mice. In male mice, contraction to serotonin increased by ≈40% and 2.5-fold in male eNOS and eNOS mice, respectively. Contraction to serotonin was more than doubled in female eNOS mice and increased >5-fold in arteries from eNOS mice. In contrast, maximum vasoconstriction to U46619 was similar in male and female eNOS, eNOS, and eNOS mice. Relaxation to acetylcholine was not different in male and female eNOS or eNOS mice but was absent in eNOS mice. These findings suggest that the contraction of carotid arteries to serotonin is influenced by the sex of the animal. eNOS deficiency in gene-targeted mice is associated with enhanced contraction to serotonin, particularly in female mice, providing direct evidence that eNOS is a major determinant of vascular effects of serotonin. The results with eNOS mice suggest a “gene-dosing” effect for vascular responses to serotonin.