# Netrin-1 and Netrin-1 Preconditioned EPCs in Vascular Protection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $458,648

## Abstract

ABSTRACT
The application aims to identify potential roles and molecular mechanisms of netrin-1 and netrin-1 pre-conditioned
endothelial progenitor cells (EPCs) in vascular protection, specifically related to their anti-restenosis and anti-
atherosclerosis effects. Four entirely novel hypotheses will be addressed: 1) Netrin-1 pre-conditioning protects
EPCs from oxidative stress induced apoptosis through PI3K-dependent p70s6 kinase activation and Bim inhibition;
In addition, mechanistic pathways mediating novel regulatory miRNAs-dependent enhancement of EPC survival by
netrin-1 will be fully delineated. By targeting these novel mechanisms, EPC functions can be augmented to
attenuate restenosis and atherosclerosis, leading to development of novel therapeutics. 2) Netrin-1 inhibits
monocyte activation in a UNC5B (repellant class of netrin-1 receptor)-dependent fashion; and that UNC5B is
innovatively regulated by a p47phox-dependent mechanism. Therefore, inhibition of p47phox may potentiate the
beneficial effects of netrin-1 in limiting restenosis and atherosclerosis via attenuation of UBC5B expression and
UNC5B-dependent monocyte activation. Netrin-1 also inhibits VSMC migration and proliferation via a
NO/cGMP/PKG/p38MAPK-dependent mechanism. 3) Administration with netrin-1 or netrin-1 preconditioned EPCs
attenuates atherosclerosis in high-fat fed apoE null and LDLR deficient mice. These protective effects are at least in
part attributed to augmented EPC function and abrogated monocyte activation, as well as attenuated VSMC
proliferation and migration. 4) Endogenous netrin-1 signaling is physiologically protective against restenosis and
atherosclerosis, loss of which exaggerates vascular pathologies. We hypothesize that femoral artery injury/high-fat
feeding into the netrin-1 or netrin-1/apoE double knockout mice will result in exaggerated restenosis/atherosclerosis.
The overall hypothesis is that administration of netrin-1 and netrin-1 preconditioned EPCs remarkably attenuate
restenosis and atherosclerosis via mechanisms of augmented EPC function (increased survival, proliferation and
homing) to lead to rapid re-endothelialization, attenuated monocyte and VSMC activation, as well as diminished
dyslipidemia. Endogenous netrin-1 signaling is physiologically vascular protective, amplification of which with
exogenous administration of netrin-1 is necessary to result in sufficient protection, whereas deficiency in the
endogenous signaling of netrin-1 (i.e. due to genetic defects) is prone to deteriorated vascular pathologies. Four
specific aims are designed to fully address these hypotheses, and accomplishments of the aims may establish
netrin-1, netrin-1 pre-conditioned EPCs, and modulators of related pathways as novel therapeutic options for
vascular pathologies of restenosis and atherosclerosis.

## Key facts

- **NIH application ID:** 10132380
- **Project number:** 5R01HL142951-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Hua Linda Cai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $458,648
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132380

## Citation

> US National Institutes of Health, RePORTER application 10132380, Netrin-1 and Netrin-1 Preconditioned EPCs in Vascular Protection (5R01HL142951-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132380. Licensed CC0.

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