Abstract-Reductions in uterine perfusion pressure (RUPP) in pregnant rats is associated with increased tumor necrosis factor-␣ (TNF-␣). This study was designed to determine the role of endogenous TNF-␣ in mediating changes in arterial pressure and endothelin-1 (ET-1) in RUPP rats. To achieve this goal we examined the effect of RUPP in the presence and absence of a TNF-␣-soluble receptor, etanerecept (0.4 mg/kg). Mean arterial pressure increased from 102Ϯ1 mm Hg in normal pregnant (NP) rats to 134Ϯ3 mm Hg (PϽ0.05) in RUPP rats. Serum TNF-␣ increased to 40Ϯ7.6 pg/mL in RUPP rats (nϭ24)

The initiating event in preeclampsia is thought be to reduced uteroplacental perfusion. Although we have reported previously that chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats results in hypertension and enhanced endothelin production, the factors linking placental ischemia and endothelial cell activation remain unclear. The purpose of this study was to determine the role of angiotensin II type-1 (AT1) receptor activation on endothelin production induced by serum from pregnant rats exposed to reductions in uterine perfusion. To achieve this goal, human umbilical vein endothelial cells were exposed to sera collected from RUPP rats or normal pregnant rats. Arterial pressure was significantly higher in RUPP rats (135+/-2 mm Hg) than in pregnant rats (106+/-1 mm Hg). Six hours after exposure to RUPP serum (n=17), cell media endothelin concentration was 18.4+/-2.7 pg/mL as compared with 9.22+/-1.3 pg/mL from cells exposed to serum from normal pregnant rats (n=9). Eighteen hours after exposure to RUPP serum (n=7), endothelin concentration was 30.5+/-3.8 pg/mL as compared with 12.8+/-5.3 pg/mL from cells exposed to normal pregnant rat serum (n=6). In contrast, serum from RUPP rats did not increase endothelin production in human umbilical vein endothelial cells pretreated with an AT1 receptor antagonist, losartan (15 micromol/L). Eighteen hours after exposure to RUPP serum and losartan (n=14), endothelin concentration was 21.3+/-2.2 pg/mL as compared with 16.4+/-3.3 pg/mL from cells exposed to normal pregnant rat serum and losartan (n=10). These data indicate that serum from pregnant rats exposed to reductions in uterine perfusion enhances endothelin production by endothelial cells via by AT1 receptor activation.

BACKGROUND Inflammatory cytokines such as tumor necrosis factor-α (TNF-α) may be an important link between placental ischemia and hypertension in preeclampsia. We examined the effect of 17-hydroxyprogesterone caproate (17-OHP) on TNF-α-stimulated endothelin (ET) production and hypertension during pregnancy. METHODS TNF-α-stimulated ET was examined from endothelial cells cultured in the presence and absence of progesterone. Blood pressure and tissue ET-1 were measured in the following groups of pregnant rats: controls, 17-OHP (3.32 mg/kg), TNF-α treated (50 ng/day), TNF-α treated+17-OHP. RESULTS Progesterone abolished TNF-α-stimulated ET-1 from endothelial cells. TNF-α-induced hypertension was associated with significant increases in renal and placental ET-1. Administration of 17-OHP attenuated TNF-α-induced hypertension and decreased renal ET-1. CONCLUSION Progesterone directly abolished TNF-α-stimulated ET-1 and attenuated TNF-α-induced hypertension, possibly via suppression of the renal ET-1 system. These data suggest that treatment with progesterone of hypertension associated with elevated cytokines during pregnancy may be worthy of further consideration.

Background Preeclampsia is associated with increased levels of reactive oxygen species (ROS) and the anti-angiogenic factor, soluble fms-like tyrosine kinase (sFlt-1). Moreover, recent studies have indicated that chronic sFlt-1 excess causes hypertension in pregnant animals. The purpose of this study was to evaluate the role of ROS in mediating sFlt-1 induced hypertension in the pregnant rat. Methods Mean arterial pressure (MAP), plasma sFlt-1 and tissue ROS levels were measured in the following groups: (i) pregnant controls; (ii) sFlt-1 treated pregnant rats; (iii) Tempol treated pregnant rats; (iv) sFlt-1 and Tempol treated pregnant rats. Results Mean arterial pressure increased from 104 +/−2 mmHg in pregnant control rats to 118 +/−3 mmHg (P = 0.002) in sFlt-1 infused rats. Basal and NADPH stimulated levels of tissue ROS were increased in response to excess sFlt-1 during pregnancy. Pre-treatment with Tempol attenuated oxidative stress and hypertension in response to sFlt-1. Conclusion ROS play an important role in mediating hypertension in response to chronic sFlt-1 excess during pregnancy.

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