Preeclampsia is characterized by new onset hypertension and fetal growth restriction and is associated with aberrant activation of the innate immune complement system and stressed or ischemic placenta. Previous studies have suggested a role for both endothelin and complement system activation products in new onset hypertension in pregnancy, but inter-relationships of the pathways are unclear. We hypothesized that complement activation following placental ischemia stimulates the endothelin pathway to cause hypertension and impair fetal growth. The Reduced Uterine Perfusion Pressure (RUPP) model results in hypertension and fetal growth restriction in a pregnant rat due to placental ischemia caused by mechanical obstruction of blood flow to uterus and placenta. The effect of inhibitor of complement activation soluble Complement Receptor 1 (sCR1) and endothelin A receptor (ETA) antagonist atrasentan on hypertension, fetal weight, complement activation (systemic circulating C3a and local C3 placental deposition) and endothelin [circulating endothelin and message for preproendothelin (PPE), ETA and endothelin B receptor (ETB) in placenta] in the RUPP rat model were determined. Following placental ischemia, sCR1 attenuated hypertension but increased message for PPE and ETA in placenta, suggesting complement activation causes hypertension via an endothelin independent pathway. With ETA antagonism the placental ischemia-induced increase in circulating C3a was unaffected despite inhibition of hypertension, indicating systemic C3a alone is not sufficient. In normal pregnancy, inhibiting complement activation increased plasma endothelin but not placental PPE message. Atrasentan treatment increased fetal weight, circulating endothelin and placental ETA message, and unexpectedly increased local complement activation in placenta (C3 deposition) but not C3a in circulation, suggesting endothelin controls local placental complement activation in normal pregnancy. Atrasentan also significantly decreased message for endogenous complement regulators Crry and CD55 in placenta and kidney in normal pregnancy. Results of our study indicate that complement/endothelin interactions differ in pregnancies complicated with placental ischemia vs normal pregnancy, as well as locally vs systemically. These data clearly illustrate the complex interplay between complement and endothelin indicating that perturbations of either pathway may affect pregnancy outcomes.
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health National Heart Lung and Blood Institute (Grant R15-HL109843 to J.F.R., J.S.G., and S.D.F), American Heart Association ( 17GRNT33650049 to J.F.R., S.D.F.), University of Minnesota OVPR Research Grant in Aid (J.F.R.) and the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (Grant P20GM103418 to S.D.F).
This work was supported by the National Institutes of Health National Heart Lung and Blood Institute (Grant R15-HL109843 to J.F.R., J.S.G., and S.D.F), American Heart Association (17GRNT33650049 to J.F.R., S.D.F.), University of Minnesota OVPR Research Grant in Aid (J.F.R.) and the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (Grant P20GM103418 to S.D.F). The authors acknowledge Dr. Ronald Regal, Department of Mathematics and Statistics, University of Minnesota Duluth for statistical analysis of the data. In addition, Dr. Henry Marsh, Celldex Therapeutics, Inc. (Needham, MA) is acknowledged for providing the sCR1 used in published studies that provided the archived samples from sCR1 treated animals.
- Placental ischemia