# Angiopoietin/Tie signaling regulation of vascular leakage in lung inflammation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $634,697

## Abstract

Angiopoietin/Tie signaling regulation of vascular leakage in lung inflammation
PROJECT SUMMARY
As a central feature of acute lung injury and acute respiratory distress syndrome (ARDS), vascular leakage not
only impairs gas exchange but also initiates a cascade of events that can have fatal consequences. No
treatments are currently available to reduce leakage by stabilizing the lung vasculature. This project will
determine the contributions of angiopoietin-2 (Ang2), orphan receptor Tie1, and VE-PTP, also known as
vascular endothelial protein-tyrosine phosphatase, to the regulation of Tie2 (Tek) receptor signaling and
increased vascular permeability (“leakage”) in lung injury. Building on known anti-leakage effects of
angiopoietin-1 (Ang1) and other Tie2 agonists, the project will target components of a recently described
positive feedback loop that governs the severity of vascular leakage. Inflammatory cytokines that trigger Tie1
receptor ectodomain shedding and inactivation and Tie2 signaling suppression in endothelial cells also
increase Foxo1 transcriptional activity and expression of Ang2, which sustains Tie2 inactivation and leakage.
Aim #1 will explore new approaches for reducing leakage and promoting vascular stability in lung injury by
reversing the suppression of Tie2 signaling in endothelial cells of alveolar capillaries. Experiments will
determine the contributions of Ang2 overexpression, Tie1 ectodomain shedding and inactivation, and VE-PTP-
mediated Tie2 dephosphorylation to Tie2 inactivation and leakage in lung injury. Genetic and pharmacologic
gain- and loss-of-function strategies will be used to activate Tie2, inhibit Ang2, suppress Tie1 ectodomain
shedding, and inhibit VE-PTP activity in the lung vasculature in prevention and reversal trials of sepsis and
influenza virus infection in mice. Tie1, Tie2 phosphorylation, Ang2, VE-PTP, and leakage will be assessed as
readouts. Leakage will be localized and measured by novel methods for visualizing extravasated fibrinogen
and 20-nm fluorescent microspheres at the level of individual alveolar capillaries. Aim #2 will examine the
functional and prognostic significance of elevated circulating levels of soluble Tie1 (sTie1) as a biomarker of
endothelial dysfunction in lung injury. Studies in mice will identify changes in endothelial cell Tie2 signaling that
lead to increased blood levels of sTie1 and how these relate to the severity of leakage from lung capillaries.
Parallel studies of critically ill patients will probe the clinical significance of elevated plasma levels of sTie1 in
sepsis, with or without the development of ARDS. The work will build on data from pilot studies showing 67%
mortality in 23 critically ill patients with elevated plasma levels of sTie1 and Ang2 at admission, compared to
only 8% in those with normal sTie1 and Ang2. Together, the experiments will define the functional benefit of
activating Tie2, inhibiting Ang2, suppressing Tie1 ectodomain shedding, and inhibiting...

## Key facts

- **NIH application ID:** 10186794
- **Project number:** 5R01HL143896-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Donald M McDonald
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $634,697
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186794

## Citation

> US National Institutes of Health, RePORTER application 10186794, Angiopoietin/Tie signaling regulation of vascular leakage in lung inflammation (5R01HL143896-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10186794. Licensed CC0.

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