There is a fundamental gap in understanding how placental ischemia during pregnancy leads to hypertension in the mother and intrauterine growth restriction (IUGR) of the child. In studies of hypertension in pregnancy, the research focus is on the balance of pro-angiogenic factors (vascular endothelial growth factor) and anti-angiogenic factors (soluble fms-like tyrosine kinase-1, soluble endoglin) leading to hypertension. In studies of complement system and pregnancy the research focus is on angiogenic imbalance leading to fetal loss in immune mediated events. The proposed studies test the critical mechanistic link between complement system and hypertension following placental ischemia. Long term goal: Determine the therapeutic utility of manipulating the complement system to prevent preeclampsia or minimize maternal/fetal consequences. Overall objective of the current proposal is to identify complement activation as a critical event leading to adverse maternal/fetal consequences in the reduced uteroplacental perfusion pressure (RUPP) model in the rat that closely mimics hypertension associated with preeclampsia. This model of placental ischemia in the 3rd trimester pregnant rat is characterized by angiogenic imbalance, endothelial dysfunction, hypertension and IUGR;all characteristics of preeclampsia in humans. The central hypothesis for events following placental ischemia is that complement activation leads to generation of the complement cleavage product C5a and placental neutrophil infiltration resulting in angiogenic imbalance, endothelial dysfunction, hypertension and IUGR.
Specific Aim #1 : Identify complement activation and generation of C5a as a critical event for placental neutrophil infiltration, angiogenic imbalance and the resultant endothelial dysfunction, hypertension, and IUGR caused by placental ischemia. In vivo studies will assess complement activation and determine the effect of inhibiting complement activation and antagonizing the C5a receptor. In vitro studies with placental explants, trophoblast cells and inflammatory cells will determine if complement activation directly alters angiogenic balance in the placenta or requires infiltration of inflammatory cells.
Specific Aim 2 : Identify placental neutrophil infiltration as a critical event leading to angiogenic imbalance and the resultant endothelial dysfunction, hypertension, and IUGR caused by placental ischemia. In vivo studies will assess the effect of neutrophil depletion. The proposed research is innovative because it couples essential expertise in the complement system and inflammation with animal models of pregnancy induced hypertension to investigate novel mechanistic pathways that precede angiogenic imbalance and lead to adverse consequences for mother and child. These studies will determine the importance of complement system activation and neutrophil accumulation as a cause of hypertension and IUGR in complicated pregnancies. This contribution will be significant because it will determine if manipulation of the complement system or neutrophil accumulation is a feasible therapeutic option for prevention and/or treatment of hypertension associated with preeclampsia.
The proposed research is relevant to public health because preeclampsia and related hypertensive disorders of pregnancy affect ~10% of all pregnancies in the United States, significantly impacting the health of both mother and child. Preeclampsia is a leading cause of maternal death (18%) and premature birth (15%). The project is relevant to the mission of NIH because mechanistic studies linking complement system activation to hypertension and intrauterine growth restriction will determine the potential therapeutic benefit of manipulating the complement system or neutrophil infiltration to treat and/or prevent the hypertension of preeclampsia and potentially minimize adverse consequences for both mother and child.
| Regal, Jean F; Laule, Connor F; McCutcheon, Luke et al. (2018) The complement system in hypertension and renal damage in the Dahl SS rat. Physiol Rep 6:e13655 |
| Akhaphong, Brian; Lockridge, Amber; Jo, Seokwon et al. (2018) Reduced Uterine Perfusion Pressure Causes Loss of Pancreatic Beta Cell Area but Normal Function in Fetal Rat Offspring. Am J Physiol Regul Integr Comp Physiol : |
| Regal, Jean F; Burwick, Richard M; Fleming, Sherry D (2017) The Complement System and Preeclampsia. Curr Hypertens Rep 19:87 |
| Laule, Connor F; Wing, Cameron R; Odean, Evan J et al. (2017) Effect of nicotine on placental ischemia-induced complement activation and hypertension in the rat. J Immunotoxicol 14:235-240 |
| Regal, Jean F; Strehlke, Megan E; Peterson, Jenna M et al. (2016) Role of IgM and angiotensin II Type I receptor autoantibodies in local complement activation in placental ischemia-induced hypertension in the rat. Mol Immunol 78:38-47 |
| Regal, Jean F; Dornfeld, Kenneth J; Fleming, Sherry D (2016) Radiotherapy: killing with complement. Ann Transl Med 4:94 |
| Regal, Jean F; Gilbert, Jeffrey S; Burwick, Richard M (2015) The complement system and adverse pregnancy outcomes. Mol Immunol 67:56-70 |
| Regal, Jean F; Lillegard, Kathryn E; Bauer, Ashley J et al. (2015) Neutrophil Depletion Attenuates Placental Ischemia-Induced Hypertension in the Rat. PLoS One 10:e0132063 |
| Gilbert, Jeffrey S; Gillham, Haley E; Regal, Jean F (2014) Down but not out: an emerging role for the B-type endothelin receptor in placental ischemia-induced hypertension. Hypertension 64:461-2 |
| Lillegard, Kathryn E; Loeks-Johnson, Alex C; Opacich, Jonathan W et al. (2014) Differential effects of complement activation products c3a and c5a on cardiovascular function in hypertensive pregnant rats. J Pharmacol Exp Ther 351:344-51 |
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