The greater incidence of hypertension and coronary artery disease in men and postmenopausal women compared with premenopausal women has been related, in part, to gender differences in vascular tone and possible vascular protective effects of the female sex hormones estrogen and progesterone. However, vascular effects of the male sex hormone testosterone have also been suggested. Estrogen, progesterone, and testosterone receptors have been identified in blood vessels of human and other mammals and have been localized in the plasmalemma, cytosol, and nuclear compartments of various vascular cells, including the endothelium and the smooth muscle. The interaction of sex hormones with cytosolic/nuclear receptors triggers long-term genomic effects that could stimulate endothelial cell growth while inhibiting smooth muscle proliferation. Activation of plasmalemmal sex hormone receptors may trigger acute nongenomic responses that could stimulate endothelium-dependent mechanisms of vascular relaxation such as the nitric oxide-cGMP, prostacyclin-cAMP, and hyperpolarization pathways. Additional endothelium-independent effects of sex hormones may involve inhibition of the signaling mechanisms of vascular smooth muscle contraction such as intracellular Ca2+ concentration and protein kinase C. The sex hormone-induced stimulation of the endothelium-dependent mechanisms of vascular relaxation and inhibition of the mechanisms of vascular smooth muscle contraction may contribute to the gender differences in vascular tone and may represent potential beneficial vascular effects of hormone replacement therapy during natural and surgically induced deficiencies of gonadal hormones.

Abstract-Placental ischemia during pregnancy is associated with increased plasma cytokines such as interleukin-6 (IL-6), which may contribute to increased vascular resistance and hypertension of pregnancy. We tested the hypothesis that an increase in plasma IL-6 during pregnancy is associated with impaired endothelium-dependent relaxation, enhanced vascular contraction, and hypertension. Systolic blood pressure was measured in virgin and pregnant Sprague-Dawley rats non-treated or infused with IL-6 (200 ng/kg per day for 5 days). Isometric contraction was measured in isolated aortic strips, and endothelial nitric oxide (NO) synthase (eNOS) was measured in aortic homogenate using Western blots. Blood pressure was greater in IL-6 -infused (146Ϯ3) than in control pregnant rats (117Ϯ2 mm Hg). In endothelium-intact vascular strips, phenylephrine (Phe) caused greater increase in active stress in IL-6 -infused (maximum: 10.6Ϯ0.6) than in control pregnant rats (maximum: 4.1Ϯ0.3ϫ10 4 N/m 2 ). Acetylcholine (ACh)-induced relaxation of Phe contraction and vascular eNOS protein and nitrite/nitrate production were less in IL-6 -infused than in control pregnant rats.Ϫ5 mol/L), inhibitor of cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in control but not IL-6 -infused pregnant rats. Endothelium removal enhanced Phe-induced stress in control but not in IL-6 -infused pregnant rats. The blood pressure and vascular Phe-induced contraction, ACh relaxation, and eNOS protein were not different between control and IL-6 -infused virgin rats. Thus, an endotheliumdependent NO-cGMP-mediated relaxation pathway is inhibited in systemic vessels of pregnant rats infused with IL-6. The results support a role for IL-6 as a possible mediator of the increased vascular resistance during hypertension of pregnancy. Key Words: blood pressure Ⅲ endothelium Ⅲ nitric oxide Ⅲ pregnancy N ormal pregnancy is associated with reduced systemic vascular resistance and arterial pressure and decreased vascular contraction to vasoconstrictor agonists. 1-3 The hemodynamic and vascular changes observed during normal pregnancy have been attributed, in part, to increased nitric oxide (NO) production by various cells, including vascular endothelial cells. 4 -8 This is supported by reports that the tissue expression and activity of NO synthase are increased during late gestation 9 -11 and that the metabolic production and plasma level of cyclic guanosine 3Ј,5Ј-monophosphate (cGMP), a second messenger of NO and a cellular mediator of vascular smooth muscle relaxation, 12 are increased during pregnancy. 13 In 3% to 5% of pregnancies, a condition called preeclampsia develops, which is characterized by increased intravascular coagulation, proteinuria, increased systemic vascular resistance ,and hypertension. 14 -16 Although preeclampsia is a major cause of maternal and fetal morbidity and mortality, the mechanisms of this disorder have not yet been clearly identified. Because of the difficulty of performing mechanistic...

Orshal, Julia M., and Raouf A. Khalil. Interleukin-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats. Am J Physiol Regul Integr Comp Physiol 286: R1013-R1023, 2004 10.1152 10. /ajpregu. 00729.2003 is elevated in plasma of preeclamptic women, and twofold elevation of plasma IL-6 increases vascular resistance and arterial pressure in pregnant rats, suggesting a role of the cytokine in hypertension of pregnancy. However, whether the hemodynamic effects of IL-6 reflect direct effects of the cytokine on the mechanisms of vascular contraction/relaxation is unclear. The purpose of this study was to test the hypothesis that IL-6 directly impairs endotheliumdependent relaxation and enhances vascular contraction in systemic vessels of pregnant rats. Active stress was measured in aortic strips isolated from virgin and late pregnant Sprague-Dawley rats and then nontreated or treated for 1 h with IL-6 (10 pg/ml to 10 ng/ml). In endothelium-intact vascular strips, phenylephrine (Phe, 10 Ϫ5 M) caused an increase in active stress that was smaller in pregnant (4.2 Ϯ 0.3) than virgin rats (5.1 Ϯ 0.3 ϫ 10 4 N/m 2 ). IL-6 (1,000 pg/ml) caused enhancement of Phe contraction that was greater in pregnant (10.6 Ϯ 0.7) than virgin rats (7.5 Ϯ 0.4 ϫ 10 4 N/m 2 ). ACh and bradykinin caused relaxation of Phe contraction and increases in vascular nitrite production that were greater in pregnant than virgin rats. IL-6 caused reductions in ACh-and bradykinin-induced vascular relaxation and nitrite production that were more prominent in pregnant than virgin rats. Incubation of endothelium-intact strips in the presence of N -nitro-L-arginine methyl ester (10 Ϫ4 M) to inhibit nitric oxide (NO) synthase, or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 10 Ϫ5 M) to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in nontreated but to a lesser extent in IL-6-treated vessels, particularly those of pregnant rats. Removal of the endothelium enhanced Pheinduced stress in nontreated but not IL-6-treated vessels, particularly those of pregnant rats. In endothelium-denuded strips, relaxation of Phe contraction with sodium nitroprusside, an exogenous NO donor, was not different between nontreated and IL-6-treated vessels of virgin or pregnant rats. Thus IL-6 inhibits endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of virgin and pregnant rats. The greater IL-6-induced inhibition of vascular relaxation and enhancement of contraction in systemic vessels of pregnant rats supports a direct role for IL-6 as one possible mediator of the increased vascular resistance associated with hypertension of pregnancy.cytokines; nitric oxide; pregnancy NORMAL PREGNANCY is associated with decreased systemic vascular resistance and arterial pressure and reduced vascular contraction in response to vasoconstrictors (15,32,41,43). The hemodynamic and vascular changes associated with normal pregnancy ...