# Mechanisms of endothelial regeneration and resolution of lung vascular injury

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $519,675

## Abstract

Project Summary. Loss of endothelial barrier integrity is central to pathogenesis of acute respiratory distress
syndrome (ARDS), a severe lung disease, associated with sepsis and trauma. Thus, homeostatic replenishment
of ECs after injury is required for the efficient formation of a stable endothelial barrier and to prevent long-lasting
lung vascular injury but the identity and source of these “reparative endothelial cells (ECs)” remains unclear.
Given the findings that ECs can convert into fibroblast-like cells (FLC) upon tissue injury and that forced
expression of the ETS family of transcription factors (e.g., ETV2) reprogram FLC into ECs, a fundamental
unanswered question is whether a shift from the “reparative” EC lineage into a non-reparative FLC lineage
impairs endothelial regeneration and thereby recovery from lung vascular injury. PTEN (Phosphatase and
TENsin homolog) is a well-known tumor suppressor and regulates key features of vascularization such as
endothelial migration and proliferation. Our Preliminary Data, showed that EC-specific conditional deletion of
PTEN markedly decreased lung EC regeneration while FLCs were increased and these mice developed lung
edema spontaneously. Further experiments showed that PTEN localized to the nucleus of ECs and maintained
the expression of endothelial transcription factor, Ets-Related Gene (ERG). Based on these intriguing
Preliminary Data, and using a range of powerful approaches such as novel genetic mouse models (inducible
dual-reporter EC-PTEN and EC-ERG null mice for lineage tracing), RNAseq and measurements of lung vascular
permeability we will investigate the hypothesis that PTEN-induced ERG pathway is a key determinant of the EC
lineage and resolution of lung-fluid balance. Our Specific Aims are: #1: to investigate the hypothesis that
EC-expressed PTEN drives endothelial cell regeneration at the expense of fibroblast-like cells and
thereby maintains the lung vascular barrier; #2: to determine (a) the role of the endothelial transcription
factor, ERG, as an effector of PTEN and a key determinant of EC lineage, and (b) to identify ERG enriched
endothelial cells through endothelial lineage tracing as intrinsic reparative ECs whose activation
promotes lung vascular regeneration and restoration of lung fluid balance. With these comprehensive
studies, we will identify for the first time the role of the PTEN-ERG cascade in maintaining the reparative EC
lineage and in resolving inflammatory lung vascular injury. We expect our studies to lay a new conceptual
framework for the development of novel therapeutic approaches exploiting PTEN as a key target for the treatment
of ARDS.

## Key facts

- **NIH application ID:** 9893019
- **Project number:** 5R01HL137169-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** DOLLY MEHTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $519,675
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893019

## Citation

> US National Institutes of Health, RePORTER application 9893019, Mechanisms of endothelial regeneration and resolution of lung vascular injury (5R01HL137169-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9893019. Licensed CC0.

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