# Pregnancy Specific Protease Activation of PAR-1 and TET2 in Preeclampsia-Implications for Therapy

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $322,144

## Abstract

Preeclampsia is a hypertensive disorder of pregnancy that is a leading cause of maternal and fetal morbidity
and mortality. The cause of preeclampsia is not known, but the pregnancy specific expression of protease-
activated receptor-1 (PAR-1) on neutrophils may hold important keys to understanding the origins of the
disease and the underlying causes of maternal organ dysfunction. We propose a novel pathway through which
elevated levels of circulating proteases in preeclamptic women activate neutrophil PAR-1, which in turn
activates RhoA kinase (ROCK), which triggers translocation of TET2 (tet methylcytosine dioxygenase) and
inflammatory transcription factors, such as NF-B, into the nucleus resulting in specific changes in DNA
methylation that cause alterations in expression of genes involved in inflammation. This would be a pregnancy
specific inflammatory mechanism because PAR-1 is only expressed on neutrophils during pregnancy. Given
the extensive vascular infiltration of neutrophils in preeclampsia, this could explain vascular dysfunction leading
to clinical manifestation of symptoms. In Aim 1 we will determine if proteases activate pregnancy neutrophils by
a PAR-1, ROCK pathway to epigenetically regulate inflammatory genes via enzymatic de-methylation of DNA
by TET2, the TET protein expressed in leukocytes. We will determine if TET2 nuclear translocation coincides
with NF-B, and if the inflammatory response induced by proteases or present in neutrophils of preeclamptic
women can be prevented by inhibition of PAR-1 or ROCK. By using a TET2 knockout cell line, we will
determine if the expression of inflammatory genes requires TET2 activation. In Aim 2 we will determine
epigenetic alterations present in neutrophils of preeclamptic women that are due to TET2. We will identify
inflammatory gene loci de-methylated by TET, and then determine if de-methylation of these loci opens up
inflammatory transcription factor binding sites as a mechanism for increased gene expression. In Aim 3 we will
evaluate if proteases activate TET2 in neutrophils of normal pregnant women resulting in a pattern for
inflammatory genes mimicking preeclampsia. These experiments will provide evidence that elevated levels of
circulating proteases in preeclampsia could mediate the in vivo activation of neutrophils. These studies will
provide new information on pregnancy specific activation of neutrophils to mediate inflammatory response, and
may provide new strategies by identifying a molecular target for the treatment of preeclampsia with PAR-1
inhibitors.

## Key facts

- **NIH application ID:** 9942279
- **Project number:** 5R01HD088386-04
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** SCOTT W WALSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,144
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942279

## Citation

> US National Institutes of Health, RePORTER application 9942279, Pregnancy Specific Protease Activation of PAR-1 and TET2 in Preeclampsia-Implications for Therapy (5R01HD088386-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9942279. Licensed CC0.

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