Abstract 040: Complement Activation in Placental Ischemia-induced Hypertension is not Dependent on Endothelin A Receptor Activation

Abstract

Early onset preeclampsia is characterized by hypertension, reduced placental perfusion, intrauterine growth restriction and increased activation of complement, part of innate immunity. We previously reported that inhibiting complement activation attenuates reduced uterine perfusion pressure (RUPP)-induced hypertension in pregnant rat and the concomitant increase in complement activation product C3a. Studies by other groups indicate endothelin A receptor (ET A ) activation plays a significant role in RUPP-induced hypertension. We hypothesized that ET A was important in placental ischemia-induced complement activation leading to hypertension. Thus, the effect of ET A antagonist atrasentan on hypertension and complement activation following placental ischemia in rat was determined. Dams received drinking water with or without 5 mg/kg/day atrasentan on gestation day (GD)13-19. On GD14, rats underwent Sham or RUPP surgery with clip placement on abdominal aorta and uterine arteries to decrease placental perfusion. On GD19, mean arterial pressure (MAP) via arterial catheter and serum C3a as indicator of complement activation were measured. RUPP surgery significantly increased MAP (109±5 mm Hg; n=7) compared to Sham (94±4 mm Hg; n=10) as well as C3a (0.36±0.08 to 0.69±0.12 units/ul). MAP was significantly reduced by atrasentan in RUPP (96±3 mm Hg; n=12) and unchanged by atrasentan in Sham (88±2 mm Hg; n=12). RUPP did not change preproendothelin mRNA in kidney cortex versus Sham, but did decrease fetal weight. In Sham, atrasentan significantly increased fetal weight (2.52±0.04 g; n=12) compared to no atrasentan (2.38±0.05 g; n=12). Importantly, atrasentan treatment did not significantly change RUPP-induced increase in C3a with 0.57±0.11 units/ul in RUPP atrasentan and 0.27±0.05 units/ul in Sham atrasentan. In contrast to other ET A antagonists (A-127722, FR-139317), the present data indicate atrasentan may promote fetal growth. However, the ET A receptor does not mediate increased complement activation and its subsequent involvement in placental ischemia-induced hypertension. Thus, our data suggest complement activation may precede involvement of endothelin in development and maintenance of high blood pressure due to placental ischemia.