# New Roles for VEGFR1 in Angiogenesis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $639,490

## Abstract

SUMMARY
The Vascular Endothelial Growth Factor (VEGF) family of ligands, and their receptor tyrosine kinase family,
comprise the VEGF-VEGFR superfamily that plays a central role in the control of blood vessel growth
(angiogenesis) in development, in adult physiology, and in over 70 diseases. VEGFs and VEGFRs are
therefore key therapeutic targets across many high-mortality and high-morbidity illnesses. However, the results
of attempts to treat diseases by targeting VEGFs and VEGFRs have been mixed. Some successes have been
seen in angiogenesis inhibition for cancer and retinopathy; but in peripheral and coronary artery diseases, over
a dozen human clinical trials delivering VEGF have failed to increase angiogenesis and perfusion, despite
success in preclinical animal models. This inability to successfully bridge treatment from animals to humans
shows that we do not sufficiently understand the multi-ligand, multi-receptor VEGF-VEGFR system. Only
through a quantitative understanding of the complex system, using a framework under which we can compare
mouse and human in a meaningful way, will we be able to successfully make predictions regarding treatment.
Most receptor work to date has focused on just one of the three VEGFRs expressed by endothelial cells,
VEGFR2, while VEGFR1, which is robustly expressed in most endothelial cells, has been relatively ignored.
However, our recent studies have shown that the plasma membrane-resident form of VEGFR1 has two
important roles in endothelial cell biology: it transduces signals itself via phosphoSTAT3, independent of
VEGFR2 activation; and it sequesters ligand, withholding it from VEGFR2 and modulating VEGFR2 signaling.
We term these the `signaling' role and the `decoy' role of VEGFR1. Both the ligand-sequestering decoy role
and signaling role of membrane-bound (m)VEGFR1 likely contribute to angiogenesis. We hypothesize that the
relative importance of signaling vs decoy depends on ligand and receptor expression, and on the regulation of
receptor trafficking and stability. In this study, we will use an integrative approach to combine the expertise of
our labs: computational modeling; mouse and human endothelial cell culture assays; and targeted therapeutic
interventions in mice and humans. This integrated approach will enable us to isolate and quantify the signaling
and decoy effects, and to define and refine their relative contributions to angiogenesis. The project goals are
to: (1) build and validate the first computational model of mVEGFR1; (2) define and quantify the signaling and
decoy roles of mVEGFR1; and (3) predict and test the effect of mVEGFR1's roles on therapies in vivo. Our
central hypothesis is that a predictive computational framework that integrates mVEGFR1 ligand-binding,
activation, trafficking, stability, and signaling will identify the modulations needed to achieve therapeutic
angiogenesis. The outcome of this study will be a better understanding of mVEGFR1 biology and its impact on
devel...

## Key facts

- **NIH application ID:** 10217193
- **Project number:** 5R01GM129074-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Feilim C Mac Gabhann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $639,490
- **Award type:** 5
- **Project period:** 2018-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217193

## Citation

> US National Institutes of Health, RePORTER application 10217193, New Roles for VEGFR1 in Angiogenesis (5R01GM129074-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10217193. Licensed CC0.

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