Reduced Endothelial NO-cGMP–Mediated Vascular Relaxation and Hypertension in IL-6–Infused Pregnant Rats

Abstract

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...

Hypertension Produced by Reductions in Uterine Perfusion in the Pregnant Rat

“…IL-6 causes endothelial dysfunction and enhanced vascular reactivity in vessels of pregnant rats. [12][13][14][15][16] We reported recently that the increase in AP produced by chronic elevations in plasma levels of TNF-␣ in pregnant rats is associated with significant increases in local production of endothelin in the kidney. 24 In addition, we reported that the increase in AP in response to TNF-␣ was completely abolished in pregnant rats treated with the endothelin receptor A antagonist.…”

“…9 Proinflammatory cytokines also affect vascular function and endothelium-derived factors involved in blood pressure regulation. [12][13][14][15][16] TNF-␣ and IL-6 have both been shown to induce structural, as well as functional, alterations in endothelial cells. 1,18 These cytokines alter the production of a number of endothelial cell substances and reduce acetylcholine-induced vasodilatation.…”

“…1,18 These cytokines alter the production of a number of endothelial cell substances and reduce acetylcholine-induced vasodilatation. 1,[12][13][14][15][16][17] Thus, endothelial dysfunction associated with many forms of hypertension may, in part, be mediated by proinflammatory cytokines.…”

Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia

“…11,12,17,[23][24][25][26][27][28][29][30][31][32][33] Because NO is an important physiological vasodilator in normal pregnancy, it follows that NO deficiency during preeclampsia has been implicated in the disease process. 18,[23][24][25][26][27][28][29][30][31][32][33] Although numerous studies indicate chronic NOS inhibition in pregnant rats produces hypertension associated with peripheral and renal vasoconstriction, proteinuria, intrauterine growth restriction, and increased fetal morbidity, 11,12,25 it is unclear whether an NO deficiency occurs in women with preeclampsia. Much of the uncertainty in this area of research originates from the difficulty in directly assessing the activity of the NO system in the clinical setting.…”

“…30,31 However, basal and stimulated release of NO from isolated vascular strips were significantly lower in the pregnant rats with placental ischemia 32 Moreover, a recent study by Orshal and Khalil found reduced endothelial NO-mediated vascular relaxation in hypertensive pregnant rats chronically infused with the inflammatory cytokine, interleukin (IL)-6. 33 …”