# Contributions of vascular chemokine receptors to cardiovascular function after traumatic-hemorrhagic shock

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $360,381

## Abstract

Project Summary/Abstract
Loss of vascular tone is characteristic for cardiovascular collapse during hemorrhagic shock and fluid
resuscitation (HS/R). Dysfunction and desensitization of α1-adrenergic receptors (ARs) is considered the
hallmark in the development of vasodilatory shock. The mechanisms responsible for α1-AR dysfunction are
unknown. The chemokines (C-C motif) chemokine ligand 2 (CCL2), CCL3, CCL5 and CCL22 have been
identified as key drivers of the initial inflammatory response to HS/R, and as early biomarkers that segregate
surviving and non-surviving trauma patients. The pathophysiological and molecular mechanisms underlying
these important clinical correlations, however, remain to be determined. We discovered that the chemokine
receptors (CRs) (C-C motif) chemokine receptor 1 (CCR1), CCR2 and CCR4, which are receptors for CCL2,
CCL3, CCL5 and CCL22, form heteromeric complexes with α1-AR in the tunica media of resistance arteries.
We provide preliminary evidence that activation of CCR2 antagonizes α1-AR mediated constriction of isolated
resistance arteries and cross-recruits b-arrestin to α1-AR, a molecular signaling event that initiates removal of
α1-AR from the plasma membrane. This leads to our main hypothesis that chemokine release during early
phases of HS/R impairs vascular tone and blood pressure regulation through activation of their CRs, which
interact with and regulate α1-AR in vascular smooth muscle cells (VSMCs). This implies that pharmacological
targeting of the CRs that interact with α1-AR will provide new therapeutic options to stabilize vascular tone and
hemodynamics, prevent cardiovascular collapse and improve resuscitation after HS. To test this hypothesis,
we propose three specific aims: 1) To determine how the CR heteromerization partners of α1-AR regulate
vascular function ex vivo. We will utilize pressure myography with isolated resistance arteries as a test
platform to define the roles of the identified CR heteromerization partners in the regulation of intrinsic vascular
function and vasopressor responsiveness. 2) To test how pharmacological targeting of the CR
heteromerization partners of α1-AR modulates cardiovascular function in vivo. We will determine how
blockade and activation of CR heteromerization partners affect normal cardiovascular function, vasopressor
responsiveness and cardiovascular function during HS/R. 3) To determine the molecular mechanisms by
which the CR heteromerization partners of α1-AR regulate α1-AR function. We will determine the
mechanisms of cross-talk between the identified CRs and α1-AR, and elucidate the pathways by which the CR
heteromerization partners of α1-AR modulate α1-AR-induced signaling and VSMC contraction. New knowledge
gained from this proposal will advance our understanding of the regulation of vascular function and identify
new molecular targets that could be used to improve blood pressure control during HS/R, and in
hemodynamically instable critically ill patients i...

## Key facts

- **NIH application ID:** 10091901
- **Project number:** 1R01GM139811-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Matthias Majetschak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,381
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091901

## Citation

> US National Institutes of Health, RePORTER application 10091901, Contributions of vascular chemokine receptors to cardiovascular function after traumatic-hemorrhagic shock (1R01GM139811-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10091901. Licensed CC0.

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