# Metabolic Regulation of Endothelial Barrier Restoration Following Vascular Injury

> **NIH NIH P01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $339,491

## Abstract

Project Summary
Endothelial barrier dysfunction is a central factor in the pathogenesis of Acute Respiratory Distress Syndrome
(ARDS) and Acute Lung Injury (ALI). In recent years, considerable advances have been made in the
understanding of how intracellular signaling pathways modulate the disruption and assembly of adherens
junctions (AJs). Re-annealing of AJs is a metabolically active process. Yet, little is known about the role of
endothelial metabolism as a modulator of endothelial barrier function and restoration of lung vascular injury. Our
Supporting Data demonstrate that endothelial cells respond to inflammatory activation with upregulation of
signaling via the hypoxia-inducible factor HIF1α, and its crucial downstream metabolic target PFK-FB3, a critical
regulatory enzyme for glycolysis. This glycolytic shift is accompanied by concomitant upregulation of
mitochondrial glutamine metabolism, which compensates for the loss of mitochondrial glucose oxidation and
enables cells to use glutamine as an alternate mitochondrial TCA cycle fuel. We observed that inhibition of PFK-
FB3 prevents restoration of endothelial barrier function following lung injury, thus underscoring the adaptive role
of PFK-FB3 and increased glycolysis during endothelial barrier restoration. Based on these findings, we posit
that induction of glycolysis in lung microvessel endothelial cells serves as a homeostatic mechanism mediating
the restoration of endothelial barrier function and lung fluid balance. In Project 2, we will pursue the following
Specific Aims: (1a) We will define the mechanisms of PFK-FB3-mediated activation of glycolysis and
compensatory glutaminolysis in lung endothelial cells as induced by inflammation and endothelial
injury, and determine the requisite role of these metabolic shifts in repairing endothelial barrier; (1b) we
will determine the spatial-temporal role of PFK-FB3-mediated activation of glycolysis in the re-annealing
of AJs and restoring endothelial barrier integrity, and (2) We will determine the role of endothelial
metabolic reprogramming via PFK-FB3 in restoring lung endothelial barrier integrity and fluid balance
following inflammatory lung injury in models of ALI. Using state-of-the-art metabolic analyses, engineered
protein constructs and biosensors as well as novel genetic mouse models, we will define the metabolic
mechanisms activated by inflammatory injury of the lung endothelium and their role in restoring the lung
endothelial barrier. Our long-term goal is to identify metabolic targets and switches that will promote and
accelerate the recovery of the endothelial barrier and normalize lung fluid balance to mitigate acute lung injury.

## Key facts

- **NIH application ID:** 9970542
- **Project number:** 5P01HL060678-20
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jalees Rehman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,491
- **Award type:** 5
- **Project period:** 2000-03-08 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970542

## Citation

> US National Institutes of Health, RePORTER application 9970542, Metabolic Regulation of Endothelial Barrier Restoration Following Vascular Injury (5P01HL060678-20). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970542. Licensed CC0.

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