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

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $401,250

## Abstract

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.

## Key facts

- **NIH application ID:** 10521835
- **Project number:** 1R01HL160881-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Manu Banadakoppa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $401,250
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521835

## Citation

> US National Institutes of Health, RePORTER application 10521835, Evaluating role of complement activation induced signaling pathways in preeclampsia pathology using a novel complement activation-based mouse model (1R01HL160881-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10521835. Licensed CC0.

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