# Pulmonary Vascular Regeneration via Venous Endothelial Progenitors

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $27,122

## Abstract

Project Summary
Respiratory viral infections represent a major risk factor for the development of acute respiratory distress
syndrome. Moreover, severe influenza injury can result in ineffective repair and persistent loss of pulmonary
function. The lung endothelium, especially the microvasculature, is damaged due to the robust inflammatory
response from viral infections, but the mechanisms of pulmonary endothelium regeneration after severe
influenza injury are not completely elucidated despite the vasculature’s central importance in gas exchange. This
proposal aims to answer fundamental questions about pulmonary vascular regeneration regarding the origin of
vascular progenitor(s) and the mechanisms driving endothelial repair in response to influenza injury. We recently
demonstrated that COUP-TFII, a vein-specifying transcription factor enriched in proliferating endothelial cells, is
necessary for lung regeneration. The venous endothelium is increasingly recognized as a vascular progenitor
population for endothelial regeneration in various organs in zebrafish and mice, suggesting that pulmonary veins
/ venules may similarly harbor potent progenitor cells. In my own preliminary data, I observed that venous
endothelial cell clones are highly proliferative and can span into the microvasculature. Aim 1 of this proposal will
utilize clonal lineage tracing and orthotopic transplantation techniques to determine if the venous endothelium
harbors potent progenitor and proliferative potential during lung regeneration. The second focus of this proposal
is to elucidate the mechanisms and interactions that are required for endothelial proliferation. Along with
expression of venous markers, proliferating endothelial cells secrete C-C Motif Chemokine Ligand 2 (CCL2), a
chemokine involved in mediating the inflammatory response during injury. The CCL2-CCR2 signaling axis
promotes inflammatory angiogenesis in mice through recruitment of monocyte derived inflammatory
macrophages, indicating a role for endothelial-specific release of CCL2 during tissue repair. Therefore, Aim 2
will employ conditional, temporal deletion of CCL2 in endothelial cells and clodronate-liposome mediated
depletion of macrophages to investigate if loss of endothelial-derived CCL2 impacts endothelial proliferation and
consequent angiogenic repair. This proposal will address the central hypothesis that a pulmonary endothelial
progenitor population present in the preexisting venous endothelium secretes CCL2 to recruit interstitial
monocytes to provide an angiogenic niche. Completion of this project will validate the venous endothelium as an
important contributor to pulmonary regeneration and will also facilitate identification of specific paracrine /
immune pathways that could allow for precise regulation and preservation of the beneficial immune response.

## Key facts

- **NIH application ID:** 10916484
- **Project number:** 5F31HL165636-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Joanna Wong
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $27,122
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916484

## Citation

> US National Institutes of Health, RePORTER application 10916484, Pulmonary Vascular Regeneration via Venous Endothelial Progenitors (5F31HL165636-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916484. Licensed CC0.

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