# TRPC4-DEPENDENT CYTOSOLIC CALCIUM SIGNALS COORDINATE INTERENDOTHELIAL FORCES THAT ELICIT GAP FORMATION

> **NIH NIH F32** · UNIVERSITY OF SOUTH ALABAMA · 2020 · $44,513

## Abstract

Project Summary
 Acute lung injury is a disorder of acute inflammation that causes disruption of the pulmonary endothelial barrier
and contributes a significant amount of morbidity and mortality in the intensive care unit. Endothelial barrier integrity
is critically determined by endothelial cytosolic calcium ion (Ca2+) transients that are activated by the plasma
membrane store-operated Ca2+ entry (ISOC) channels. One of the channel subunits, canonical transient receptor
potential 4 (TRPC4) protein, critically regulates channel activation and Ca2+ influx. Elevation of cytosolic Ca2+ is
sufficient to induce interendothelial gaps in extra-alveolar segments and cause pulmonary edema. However, the
mechanism by which TRPC4-dependent Ca2+ influx disrupts adherens junction and coordinates
interendothelial forces is poorly understood and is the focus of this application.
 Cytosolic Ca2+ is not stable but rather fluctuates within a confluent endothelial monolayer. TRPC4 contributes to
these basal cytosolic Ca2+ transients. Inflammatory agonists induce Ca2+ influx by activating the TRPC4 ISOC
channel leading to a marked elevation of cytosolic Ca2+, which causes endothelial cell retraction and gap formation.
However, it is unknown whether these TRPC4-dependent transient increases in cytosolic Ca2+ cause increases
in the coordination of interendothelial forces, interendothelial gap formation, and lung edema.
 Inflammatory diseases are related to changes in mechanical properties of cells and tissues. Intercellular
forces are spatially heterogeneous, highly cooperative, and aligned into force chains. During inflammation,
disruption of the vascular endothelial barrier is partially initiated through cytoskeletal contraction of a group of
cells. The resulting increased contractile forces propagate across neighboring cells via intercellular junctions to
increase interendothelial force coordination and correlation, increase intracellular force alignment and extend
force chains far outside the gap regions. A large accumulation of contractile forces may eventually exceed the
maximum force that an adherens junction can withstand and cause the formation of an interendothelial gap. An
interendothelial gap also may form at a tri-junctional (tricellular junction) point where force chains are
misaligned and may pull the adherens junction apart. However, it is unknown how TRPC4-dependent cytosolic
Ca2+ transients are related to interendothelial force correlation at baseline and after agonist challenge. This proposal
tests the overall HYPOTHESIS that TRPC4 activation triggers unique cytosolic Ca2+ transients that are sufficient to
increase interendothelial force correlation and promote gap formation, pulmonary permeability, and pulmonary
edema.

## Key facts

- **NIH application ID:** 9998025
- **Project number:** 5F32HL144040-03
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** NINGYONG XU
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $44,513
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-06-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998025

## Citation

> US National Institutes of Health, RePORTER application 9998025, TRPC4-DEPENDENT CYTOSOLIC CALCIUM SIGNALS COORDINATE INTERENDOTHELIAL FORCES THAT ELICIT GAP FORMATION (5F32HL144040-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998025. Licensed CC0.

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