# Impact of Trauma and its Products on Vascular Endothelial Function

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $300,300

## Abstract

Severe trauma can overwhelm our endogenous hemostatic systems, and cause refractory coagulopathy and
inflammation with potentially dire consequences. Paradoxically, regular exercise, which is perceived as
improving our defenses against trauma, increases microscopic internal injury and thereby byproducts of
cellular damage, such as histones, suggesting a counterintuitive protective or adaptive function of microscopic
internal injuries. This concept has the potential to completely remold our view of the vascular response to
trauma and can provide insights into new therapeutic targets. Our lack of understanding of how vascular
endothelial cells (ECs), which line all blood vessels, sense the spectrum of trauma, and translate the signals of
trauma into changes in vascular and immune functions, represents a significant void—but also an opportunity
for clinical intervention.  Our overall hypothesis is that histone-induced endothelial Ca2+ signaling is the
translator of trauma to vascular functions. We will initially focus on two Ca2+ influx pathways, the polymodal
transient receptor potential vanilloid 4 (TRPV4) ion channel, and the ionotropic purinergic receptor P2X7. In
Aim 1, we explore the nature of EC Ca2+ signals, based on our novel data, which suggests that physiological
levels of histones engage TRPV4 channels, and trauma levels activate P2X7 to induce Ca2+ entry. In Aim 2,
we explore the functional consequences of histone-induced Ca2+ signaling on vascular responses, and test
potential strategies to protect blood vessels from endothelial dysfunction after trauma. The proposed research
project is expected to significantly advance the continuum of research needed to improve clinical outcomes in
trauma. Moreover, it has the potential to radically change our view of endothelial cell biology, providing an
enduring and sustained impact on our broader understanding of small vessels in health and disease.

## Key facts

- **NIH application ID:** 9978883
- **Project number:** 5R01GM123010-04
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Kalev Freeman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $300,300
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978883

## Citation

> US National Institutes of Health, RePORTER application 9978883, Impact of Trauma and its Products on Vascular Endothelial Function (5R01GM123010-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978883. Licensed CC0.

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