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(Hypertension. 2008;52:1161.)
© 2008 American Heart Association, Inc.

Original Articles

Hypertension in Response to Chronic Reductions in Uterine Perfusion in Pregnant Rats

Effect of Tumor Necrosis Factor- Blockade

Babbette LaMarca; Josh Speed; Lillian Fournier; Sara A. Babcock; Hunter Berry; Kathy Cockrell; Joey P. Granger

From the Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson.

Correspondence to Joey P. Granger, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505. E-mail jgranger{at}physiology.umsmed.edu

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 102±1 mm Hg in normal pregnant (NP) rats to 134±3 mm Hg (P<0.05) in RUPP rats. Serum TNF- increased to 40±7.6 pg/mL in RUPP rats (n=24) versus 14.8±3.3 pg/mL (n=16; P<0.05) in NP rats. Administration of etanerecept decreased TNF- in RUPP rats (n=20) to 17.2±3 pg/mL and mean arterial pressure to 118±2 mm Hg (P<0.05). Tissue ET-1 decreased in etanerecept-treated RUPP rats compared with control RUPP rats. The direct effect of TNF- blockade on endothelial activation in response to placental ischemia was examined in human umbilical vein endothelial cells. ET-1 secreted from human umbilical vein endothelial cells treated with RUPP serum was 59.2+16 pg/mg and decreased when etanerecept was added to the medium with RUPP serum (7.60±0.77 pg/mg), as well as in response to serum from etanerecept-treated RUPP rats (7.30±0.55 pg/mg; P<0.001). ET-1 secreted from human umbilical vein endothelial cells was 15.6±2 pg/mg when treated with NP serum. These data support the hypothesis that endogenous TNF- is an important stimulus for ET-1 in response to placental ischemia and is important in mediating endothelial cell activation and hypertension during pregnancy.

Key Words: hypertension • pregnancy • inflammation • cytokines • endothelial activation

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