Antagonism of complement C5a receptor but not C3a receptor attenuates placental ischemia‐induced endothelial dysfunction in rat (1084.8)

Abstract

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