# Mechanisms of Angiogenesis in ROP

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $377,723

## Abstract

PROJECT SUMMARY/ABSTRACT
Agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) offer benefits over
standard care laser treatment of the peripheral avascular retina in severe retinopathy of prematurity (ROP).
Our lab provided proof of concept that regulating VEGF receptor 2 (VEGFR2) signaling in retinal endothelial
cells (ECs) not only inhibited disordered intravitreal neovascularization (IVNV) in severe ROP, but also
facilitated ordered EC division to allow vascularization into peripheral avascular retina (VPAR). VPAR occurs
after intravitreal anti-VEGF treatment in infants with ROP, but reactivation with IVNV is difficult to distinguish
from VPAR. To avoid complications from reactivated IVNV, clinicians tend to treat all new angiogenesis, but
laser reduces potential VPAR and associated expanded visual field. Also, some anti-VEGFs reduce systemic
VEGF levels with reports of adverse events in treated infants. There is the need to safely target pathologic
VEGFR2 signaling to only inhibit IVNV and not VPAR. Our lab strives to understand signaling mechanisms that
permit VPAR but inhibit IVNV in ROP without damaging the retina or the infant. We found that specifically in
retinal ECs, regulation at the level of VEGF receptor 2 extended vascularization into the peripheral avascular
retina, whereas endothelial STAT3 or the erythropoietin receptor (EPOR) either increased or inhibited IVNV. In
our novel retinal EC culture model, we distinguished VEGF-activated tyrosine sites on the C-terminal domain
(CTD) of VEGFR2. Sustained VEGFR2 signaling, important in p-ERK-mediated IVNV, activated the tyrosine
(Y1175) site but not the Y1214. We also found that the adaptor proteins, MEMO1 and IQGAP1, sustained
signaling through VEGFR2 leading to disordered or invasive angiogenesis in disease models. In transgenic
humanized mice, signaling through the EPOR improved retinal function following oxygen induced damage.
Based on our findings, we developed the hypothetical framework that regulation of angiogenesis leads to
IVNV or VPAR and is mediated by signaling events involving1) activation of tyrosine phosphorylation sites on
VEGFR2 or 2) adaptor proteins, e.g., MEMO1, IQGAP1, and that 3) crosstalk between EPOR and VEGFR2
signaling provides retinal vascular/neural protection. We propose 3 aims to test the prediction that: 1) IVNV will
be increased by OIR- induced VEGF signaling through VEGFR2 in mice expressing mutant Y1212 (analog of
human Y1214); 2) to test prediction that adaptor protein, MEMO1, interferes with Y1175 activation, whereas
adaptor protein, IQGAP1, leads to Y1175 activation, retinal EC proliferation and IVNV; and 3) To test the
prediction that crosstalk between VEGFR2 and EPOR signaling supports polarized retinal EC migration, as in
VPAR, and that recovery of retinal neural function through EPOR involves EPOR-mediated vascular protection
against high oxygen-induced damage. Methods include: novel mice with CRISPR-engineered...

## Key facts

- **NIH application ID:** 10884722
- **Project number:** 2R01EY015130-21
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Mary Elizabeth Ruth Hartnett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $377,723
- **Award type:** 2
- **Project period:** 2004-12-02 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884722

## Citation

> US National Institutes of Health, RePORTER application 10884722, Mechanisms of Angiogenesis in ROP (2R01EY015130-21). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10884722. Licensed CC0.

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