# Endothelial S1PR1 Regulation and Resolution of Lung Vascular Permeability

> **NIH NIH P01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $342,451

## Abstract

Project Summary
Endothelial barrier dysfunction is a central factor in the pathogenesis of protein-rich lung edema and lung
inflammation, the hallmarks of acute respiratory distress syndrome (ARDS). However, attempts to develop
therapies against crucial element of the disease involving severe disruption of lung vascular endothelial barrier
and the progression of protein-rich edema formation thus far have not been successful. The endothelial cell-
expressed G-protein coupled receptor sphingosine-1-phosphate receptor-1 (S1PR1), upon ligation by the
bioactive lipid sphingosine-1-phosphate (S1P) is an important lung vascular barrier protective mechanism at
the level of adherens junctions (AJs). In following the dynamics of cell surface expression of S1PR1, we have
made the key observations that S1PR1 expression was decreased during onset of lung vascular injury by
endotoxin on the basis of phosphorylation at Tyr143-induced internalization of the receptor. S1PR1 was
however re-synthesized resulting in its re-localization to the cell surface during the resolution phase of vascular
injury. These temporal findings suggest that re-establishing the pool of cell surface S1PR1 may be crucial for
effectiveness of S1P in repairing the lung endothelial barrier. In addition, we observed that S1PR1 once at the
cell surface interacted with vascular endothelial growth factor receptor 2 (VEGFR2), suggesting that this
interaction may also play an important role in the endothelial barrier re-annealing function of S1P. These
observations raise fundamental questions about how S1PR1 is re-synthetized, means by which its cell surface
retention is regulated, and the importance of S1PR1 interaction with VEGFR2 in regulating the repair of the
lung vascular barrier. Thus, in Project 3 we will pursue the following Specific Aims: (i) we will determine
transcriptional regulation of S1PR1 synthesis, specifically the role of the transcription factor Sox2 in
regulating endothelial barrier repair and resolution of lung vascular injury; (ii) we will investigate the
role of the tyrosine phosphatase SHP-1 in regulating dephosphorylation of the crucial Tyr143 phospho-
switch and its involvement in mediating endothelial cell surface retention and responsiveness of
S1PR1; and (iii) we will define the function of S1PR1/VEGFR2 interaction as a key mechanism for
restoring lung vascular integrity secondary to the stabilization of VE-cadherin at AJs. We will apply a
range of powerful approaches such as several novel genetic mouse models (e.g., S1PR1 activity reporter
mice), engineered probes, biophysical analysis of AJs, two-photon imaging analysis, and measurements of
lung vascular permeability in mice to investigate the novel concept that de novo synthesis and cell surface
retention of S1PR1 and S1PR1 interaction with VEGFR2 are required for regulating the lung endothelial barrier
repair function of S1P. With these comprehensive and mechanistic studies and through important interactions
with...

## Key facts

- **NIH application ID:** 9970543
- **Project number:** 5P01HL060678-20
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** DOLLY MEHTA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,451
- **Award type:** 5
- **Project period:** 2000-03-08 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970543

## Citation

> US National Institutes of Health, RePORTER application 9970543, Endothelial S1PR1 Regulation and Resolution of Lung Vascular Permeability (5P01HL060678-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9970543. Licensed CC0.

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