Early-onset pre-eclampsia is characterized by decreased placental perfusion, new-onset hypertension, angiogenic imbalance, and endothelial dysfunction associated with excessive activation of the innate immune complement system. Although our previous studies demonstrated that inhibition of complement activation attenuates placental ischemia-induced hypertension using the rat reduced uterine perfusion pressure (RUPP) model, the important product(s) of complement activation has yet to be identified. We hypothesized that antagonism of receptors for complement activation products C3a and C5a would improve vascular function and attenuate RUPP hypertension.

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Preeclampsia is characterized by new‐onset hypertension, abnormal placentation, endothelial dysfunction and increased activation of the complement system generating vasoactive products complement C3a and C5a. Previous studies in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia‐induced hypertension demonstrated impaired endothelial‐dependent relaxation in isolated blood vessels. In addition, inhibition of complement system activation inhibited the hypertension. Whether complement activation is responsible for the endothelial dysfunction following placental ischemia is unclear. Hypothesis: Complement activation products C3a and C5a mediate endothelial dysfunction following placental ischemia. On gestation day (GD) 14, rats underwent sham surgery or clip placement on ovarian arteries and abdominal aorta (RUPP) to cause placental ischemia and increase blood pressure. Rats were treated once daily with C5a receptor antagonist acetyl‐F‐[Orn‐P‐(D‐Cha)‐WR] (PMX53, 3 mg/kg SC), C3a receptor antagonist N2‐[(2,2‐Diphenylethoxy)acetyl]‐L‐arginine (SB290157, 5 mg/kg IV) or vehicle (10% ethanol/saline) from GD14‐18. On GD19, blood pressure was determined via carotid artery and mesenteric arteries removed. Mesenteric arteries (200‐400µm in diameter) were pre‐contracted with 0.44 µM thromboxane mimetic U46619. Endothelial‐dependent and independent relaxations were determined by fractional relaxation of the U46619 contraction to acetylcholine (ACh, 10 nM‐0.31 mM) and sodium nitroprusside (SNP, 7.7 nM‐0.23 mM), respectively. Maximum fractional relaxation to ACh in arteries from RUPP rats (0.68±0.06) was less than Sham (0.88±0.03; p<0.05) and RUPP rats treated with PMX53 (0.83±0.06) but not RUPP rats treated with SB290157 (0.76±0.07). Relaxation to SNP was not affected by the treatments. These data suggest that C5a, but not C3a, mediates endothelial dysfunction induced by placental ischemia. Grant Funding Source: Supported by NIH HL109843

Preeclampsia, a leading cause of maternal death and premature birth, is characterized by hypertension, compromised placental perfusion and intrauterine growth restriction. The complement system, part of the innate immune system, is activated in normal pregnancy with increased activation apparent in preeclampsia. We recently reported that inhibiting complement system activation with a soluble form of endogenous complement receptor significantly attenuated reduced uterine perfusion pressure (RUPP)-induced hypertension in the pregnant rat without affecting fetal resorptions or decreased circulating vascular endothelial growth factor. Since the vasoactive complement activation product C3a increased in serum following placental ischemia, we hypothesized that C3a is an important mediator of placental ischemia-induced hypertension. Using the RUPP model of hypertension in preeclampsia, we determined the effect of the C3a receptor antagonist SB290157 (N2-[(2,2-Diphenylethoxy)acetyl]-L-arginine) on changes in blood pressure and fetal weight following placental ischemia. On gestation day 14, clips were placed on abdominal aorta and uterine arteries to decrease placental perfusion. All dams received 5 mg/kg SB290157 or 10% ethanol/saline (Veh) iv on days 14-18. Mean arterial pressure (MAP) was measured on day 19 via arterial catheter and fetal weights were subsequently assessed. SB290157 treatment of rats that underwent sham surgery (Sham SB, n=6) did not affect either MAP or fetal weights compared to Sham Veh. MAP increased in RUPP Veh rats compared to Sham Veh (RUPP Veh, n=7, 109±2 mm Hg; Sham Veh, n=7, 94±2; p<0.05) and average fetal weights decreased (Sham Veh, 2.52±0.07 g; RUPP Veh, 2.24±0.07 g; p<0.05). Treatment of RUPP rats with SB290157 attenuated increased MAP (RUPP Veh, 109±2 mm Hg; RUPP SB, n=9, 101±2; p<0.05) but did not prevent decreased fetal weight (RUPP Veh, 2.24±0.07 g; RUPP SB, 2.20±0.07 g). These data suggest C3a is partly responsible for placental ischemia-induced hypertension and provide important new evidence to support a link between complement activation and hypertension. Inhibitors of complement activation or C3a antagonists may be viable new treatment strategies for managing new-onset hypertension in preeclampsia.