Autoantibodies to the Angiotensin Type I Receptor in Response to Placental Ischemia and Tumor Necrosis Factor in Pregnant Rats

Circulating factors, such as agonistic autoantibodies to the angiotensin II type 1 (AT1) receptor (AT1-AAs), and inflammatory cytokines, including tumor necrosis factor (TNF), are suggested to be important links between placental ischemia and hypertension in preeclamptic women. The purpose of this study was to determine the role of placental ischemia and TNFin stimulating the AT1-AA and the importance of AT1 receptor activation in mediating hypertension during reductions in uterine perfusion pressure (RUPP) and chronic TNFexcess in pregnant rats. Increased mean arterial pressure in RUPP pregnant rats (122 1 mm Hg RUPP versus 101 1 mm Hg normal pregnant [NP]; P 0.001) was associated with increased circulating TNF(RUPP 48 13 pg/mL versus N 8 1 pg/mL; P 0.05) and AT1-AA (RUPP 15.3 1.6 U versus NP 0.6 0.3 U; P 0.001). Moreover, TNF–induced hypertension (97 2 to 112 2 mm Hg; P 0.05) in pregnant rats was associated with AT1-AA production (TNFrats 9.2 2.3 U versus NP rats 1.0 0.8 U; P 0.05). To determine the importance of AT1 receptor activation in mediating hypertension in RUPP– and TNF–treated rats, we administered an AT1 receptor antagonist to RUPP–, TNF–treated, and NP rats. Blood pressure responses were attenuated in RUPP rats ( 32 mm Hg versus 20 mm Hg, NP; P 0.001), as well as in TNF–treated rats ( 10 mm Hg versus 5 mm Hg, NP; P 0.05). Collectively, these data indicate that placental ischemia and TNFare important stimuli of AT1-AA, and activation of the AT1 receptor appears to, in part, mediate hypertension produced by RUPP and TNFin pregnant rats. (Hypertension. 2008;52:1168-1172.)