Evaluating role of complement activation induced signaling pathways in preeclampsia pathology using a novel complement activation-based mouse model

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Preeclampsia (PE) is a pregnancy-specific syndrome and several putative mechanisms have been implicated in the pathogenesis of PE including complement (C) cascade activation. C activation byproducts in the circulation are elevated with pregnancy in women and they are further elevated significantly in PE women. Placental deposition of C activation byproducts is also significantly elevated in PE compared to normotensive women. The semi-allogenic nature of fetus/placenta induces maternal C cascade activation. To understand the cause-and- effect relation between C activation and pregnancy hypertension, it is essential to gain insight into the mechanistic pathways that link placental C activation to pregnancy hypertension and fetal growth restriction with the view of targeting these pathways for potential therapeutic discoveries. One possible mechanism is that C activation may promote systemic antiangiogenic and proinflammatory milieu, maternal vascular dysfunction, hypertension and renal pathological changes. Further, C activation may induce placental fibrin deposition due to crosstalk with coagulation system, promoting fetal growth restriction. In this application we will determine the mechanisms that link C activation to pregnancy hypertension and fetal growth restriction using a novel complement activation-based mouse model. This transgenic mouse model allows us to downregulate Crry in an inducible, conditional and placenta specific manner and study its effects on various maternal systems. Specific aim 1. To assess if placenta specific C activation promotes systemic antiangiogenic and proinflammatory milieu, hypertension, maternal vascular dysfunction, and renal pathology through C3a-C3aR and/or C5a-C5aR, STAT3 and ERK pathways. Hypothesis: C activation during pregnancy promotes increased systemic levels of antiangiogenic (sFLT1, sEng) and proinflammatory molecules (TNF-α, IL-6 and IL-8), reduced relaxation and increased contractile responses (vascular dysfunction) of maternal peripheral arteries, hypertension, defective uterine spiral artery (SA) remodeling, and glomerular endotheliosis (renal pathology) through C3a-C3aR/C5a-C5aR, STAT3 and ERK pathways. Further, inhibition of C activation using specific inhibitor CR2-Crry ameliorates these C induced changes. Specific aim 2. To test the hypothesis that C activation induces placental fibrin deposition through its crosstalk with coagulation system promoting fetal growth restriction. Hypothesis: C activation promotes fetal growth restriction by reducing fetal blood supply due to placental peri-villous fibrin deposition through the disruption of tissue factor (TF) and von Willebrand factor (vWF) homeostasis. C activation directly through C5a-C5aR signaling and indirectly through proinflammatory cytokines IL6, IL8 and TNF-α induces the upregulation of TF, plasminogen activator inhibitor 1 and vWF by endothelial cells and downregulates the ADAMTS-13 in liver.