# Focal adhesion kinase regulation of lung vascular permeability and edemagenesis

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $477,836

## Abstract

Project Summary. Increased lung microvascular permeability, resulting in protein-rich alveolar edema and
chronic inflammation, causes ARDS (Acute Respiratory Distress Syndrome), the lethal form of acute lung injury
(ALI). During the last funding cycle, we demonstrated that endothelial cell (EC)-specific deletion of focal adhesion
kinase (FAK) disrupts adherens junctions, causing chronic pulmonary edema. We also showed that FAK is
markedly reduced in lungs of ARDS patients. These findings suggest that FAK expression is critical for
endothelial barrier repair and hence lung-fluid homeostasis. Cellular therapy can resolve inflammatory lung
vascular injury in animal models, but bone marrow-derived mesenchymal stem cells (MSCs) or MSC-derived
exosomes failed to do so in EC-FAK-/- mice. In investigating the role of EC-FAK in regulating the effectiveness
of cellular therapy in resolving lung vascular injury, we made the fundamental observation that EC-FAK is
required to maintain the expression of sphingosine-1-phosphate receptor1 (S1PR1) in ECs, which is known to
strengthen the endothelial barrier and prevent lung injury. Thus, we postulated that impaired SIPR1 synthesis is
responsible for defective endothelial barrier repair in EC-FAK-/- mice and for the loss of efficacy of stem cell
therapy. Intriguingly, S1PR1 expression and barrier function could be rescued in FAK-depleted ECs following
transduction of the transcription factor, Kruppel like factor 2 (KLF2), indicating that FAK functions by upregulating
KLF2 activity. Active KLF2 thus overcomes FAK depletion by restoring S1PR1 expression and function. These
findings led to our second seminal observation that loss of KLF2 transcriptional activity in EC-FAK-/- mice is due
to epigenetic modification of KLF2-DNA caused by activation of DNA methyltransferase 3a (DNMT3a). DNMT3a
converts cytosine to 5-methylcytosine (5mc) repressing gene transcription. Hence, DNMT3a methylation of the
KLF2 promoter led to impaired S1PR1 synthesis and barrier repair. Based on these findings, the planned
research will define the novel role of FAK in inducing EC barrier repair following injury by suppressing epigenetic
modification of KLF2, thereby enabling S1PR1 transcription and function. We will use state of the art approaches,
including EC specific knockout mice, cellular and nuclear imaging and biophysical approaches such as
measurement of cellular tension to establish this concept. Our Specific Aims are: #1: to address the concept
that FAK maintenance of S1PR1 transcription in the endothelium is required for intrinsic endothelial
barrier repair and thereby for resolving lung vascular injury, and #2: to define the role of FAK
suppression of endothelial KLF2-DNA methylation by DNMT3a as a mechanism for S1PR1 synthesis by
KLF2 and the role of this pathway in restoring endothelial barrier integrity, resolving lung vascular injury
and promoting tolerance to secondary lung injury in EC-FAK-/- mice. We believe our studies will...

## Key facts

- **NIH application ID:** 10136065
- **Project number:** 5R01HL084153-12
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** DOLLY MEHTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $477,836
- **Award type:** 5
- **Project period:** 2007-01-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136065

## Citation

> US National Institutes of Health, RePORTER application 10136065, Focal adhesion kinase regulation of lung vascular permeability and edemagenesis (5R01HL084153-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136065. Licensed CC0.

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