# Role of VE-PTP in Restoration of Lung Vascular Endothelial Junction Barrier and Fluid

> **NIH NIH P01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $351,873

## Abstract

Project Summary
Lung vascular endothelial barrier function is regulated primarily by adherens junctions (AJs) consisting of VE-
cadherin, which mediates adhesion of endothelial cells through homotypic interaction, and associated catenins.
Recently, another VE-cadherin partner Vascular Endothelial Protein Tyrosine Phosphatase, VE-PTP, has been
identified in regulating endothelial barrier function. Disassembly of AJs through internalization and subsequent
degradation of VE-cadherin disrupts the endothelial barrier resulting severe intractable protein-rich pulmonary
edema, the central pathogenic feature of ARDS. Restoration of the endothelial barrier is essential for resolving
edema, yet the mechanisms underlying re-assembly of AJs are poorly understood. Based on our Supporting
Data, in Project 1 we posit that VE-PTP is a central regulator of re-assembly of AJs that plays a critical role in
restoring endothelial barrier function through its ability to stabilize VE-cadherin at AJs. We also showed that
signaling via Hypoxia-Inducible Factors (HIFs) was required for the synthesis of VE-PTP. Notably, in addition
to VE-PTP binding to VE-cadherin, another pool of VE-PTP is associated with Tie2, the tyrosine kinase
receptor present in the endothelial plasmalemma, and which functions to restrain Tie2 activity. On the basis of
these observations, in Project 1 we will pursue the following Specific Aims: (i) we will determine the
synergistic role of (a) HIF-dependent expression of VE-PTP as an adaptive mechanism promoting the
stabilization of VE-cadherin at AJs, and (b) HIF-dependent activation of Rac1 and Cdc42 at AJs
in sealing and strengthening the AJ barrier and thus restoring lung fluid balance; (ii) we will determine
the role of VE-PTP interaction with Tie2 in regulating the repair of AJs through the activation of Tie2
signaling and the translocation of VE-PTP to VE-cadherin, and resulting in VE-cadherin stabilization;
and (iii) we will determine the therapeutic value of (a) blocking prolyl hydroxylases (PHDs) to activate
HIF-mediated transcription of VE-PTP, and (b) inhibiting Tie2 interaction with VE-PTP in restoring lung
vascular barrier function and fluid balance in models of inflammatory lung injury. We will apply a
rigorous multidisciplinary approach to define the signaling mechanisms activated by VE-PTP interaction with
VE-cadherin in restoring the integrity of lung endothelial barrier, with the intent of identifying new targets to
normalize lung fluid balance and the course of inflammatory lung injury.

## Key facts

- **NIH application ID:** 9970541
- **Project number:** 5P01HL060678-20
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Asrar B. Malik
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,873
- **Award type:** 5
- **Project period:** 2000-03-08 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970541

## Citation

> US National Institutes of Health, RePORTER application 9970541, Role of VE-PTP in Restoration of Lung Vascular Endothelial Junction Barrier and Fluid (5P01HL060678-20). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970541. Licensed CC0.

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