# Programming of PMN host-defense function during transendothelial migration. Research supplement to promote diversity in health-related research

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $62,948

## Abstract

PROJECT SUMMARY / ABSTRACT
Lung endothelial barrier integrity at the level of adherens junctions (AJs) is required for lung fluid homeostasis.
A crucial mechanism contributing to the loss of endothelial barrier integrity in conditions such as pulmonary
edema is “stress failure” of pulmonary capillaries in response to high pressure. While it is known that AJs,
comprised of VE-cadherin and associated catenin proteins, restrict endothelial permeability, little is known about
how mechanical forces, specifically vessel wall tension, control endothelial permeability and pulmonary edema.
Our Supporting Data describe the potentially important role of hydrostatic pressure in microvessels in activating
the mechanosensor Piezo1 in endothelial cells (ECs) and in increasing endothelial barrier permeability. We
observed that activation of Piezo1 induced intracellular Ca2+ signaling, which in turn, caused phosphorylation of
VE-cadherin and increased microvascular permeability. These findings have for the first time linked increased
tension to which ECs are exposed to the activation of Piezo1 and disassembly of AJs, leading to the
fundamental question “how does tension sensed at the plasma membrane of ECs by Piezo1 activate VE-
cadherin phosphorylation and thereby disrupt AJs?” In Aim 1, we will determine the role of microvessel
pressure in activating the mechanosensor channel Piezo1 in lung ECs and Piezo1’s role in regulating
endothelial permeability and lung fluid balance. We will determine whether Src dependent phosphorylation
of Piezo1 is required for Piezo1 activated Ca2+ signaling in ECs and whether this thereby mediates increased
endothelial permeability. In Aim 2, we will determine the role of Piezo1 signaling in mediating disassembly
of AJs through phosphorylation of VE-cadherin, and in increasing endothelial permeability. Here, we will
identify the signaling pathway downstream of Piezo1 activation that induces phosphorylation of VE-cadherin and
VE-cadherin endocytosis and thus disassemble the AJs. In Aim 3, we will determine the role of Piezo1 in
mediating lung vascular hyper-permeability (“stress failure”) and edema associated with left heart failure
(LHF). These studies will address the pathophysiological relevance of Piezo1 in the mechanism of pulmonary
edema resulting from LHF-induced increases in lung microvessel pressure. The above studies will be essential
for understanding the role of Piezo1 in increasing lung microvessel permeability, with the goal of identifying new
therapeutic targets for high pressure-induced pulmonary edema.

## Key facts

- **NIH application ID:** 11043672
- **Project number:** 3R01HL045638-36S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Yulia A Komarova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $62,948
- **Award type:** 3
- **Project period:** 1993-06-11 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11043672

## Citation

> US National Institutes of Health, RePORTER application 11043672, Programming of PMN host-defense function during transendothelial migration. Research supplement to promote diversity in health-related research (3R01HL045638-36S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11043672. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*