# A critical role for intracellular VEGF receptor translocation in ocular angiogenesis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $371,250

## Abstract

The collective evidence dictates that the vascular endothelial growth factor (VEGF) family is
critical for ocular angiogenesis in conditions such as diabetic retinopathy and AMD.
Investigation of VEGF action has largely focused on receptor binding events and activation of
classical downstream signal transduction cascades. Work from us and others show that VEGF
receptor (VEGFR) signaling is much more complex and an alternative pathway involves
intracellular trafficking of VEGFRs (Fig 1). We have preliminary evidence that a) endosomal
sorting, neuropilin, secretases and sumoylation appear to be key regulators of VEGFR
trafficking, b) VEGFRs in the nucleus originate from an intracellular pool, c) translocation of
VEGFRs and the relative levels of VEGFRs within subcellular compartments dictates angiogenic
outcome and d) the VEGFR1:VEGFR2 ratio at adherens junctions (AJs) and tight junctions
(TJs) changes in response to pro- and antiangiogenic factors. Based on these observations we
propose the following paradigm shifting hypothesis: VEGF-driven vascular permeability and
neovascularization are highly dependent on the targeted subcellular translocation of
specific VEGFRs in endothelial cells and that the relative levels of VEGFRs within
subcellular compartments dictates vascular permeability and angiogenic outcome. We
further postulate that endothelial-specific manipulation of the VEGFR1:2 ratio through
gene therapy will reduce vascular permeability and inhibit aberrant retinal and choroidal
neovascularization. We will test this hypothesis through the following aims. In Aim 1, we
will a) To characterizing the origin and routes of VEGFR trafficking, b) identify the nuclear
targets of VEGFR1 and VEGFR2 and assess how these targets contribute to angiogenesis, c)
assess how the nuclear level of VEGFRs dictates the angiogenic outcome and d) identify the
mechanism by which secretases, and/or sumoylation regulate trafficking of VEGFRs. In Aim 2,
we will a) determine if translocation of VEGFRs to AJs and TJs is via membrane diffusion or
endosomal trafficking and b) assess how the ratio of VEGFR1 and VEGFR2 at AJs and TJs
changes in response to pro- and antiangiogenic factors, the junctional binding partners involved,
and how this affects permeability. In Aim 3, we will assess the outcome of endothelial-specific
genetic manipulation of intracellular VEGFR levels on vascular permeability and retinal and
choroidal angiogenesis in mice. The proposed studies will significantly advance our mechanistic
understanding of aberrant ocular angiogenesis and will identify new potential therapeutic targets
for the inhibition of pathological ocular angiogenesis.

## Key facts

- **NIH application ID:** 9920715
- **Project number:** 5R01EY028861-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Michael Edwin Boulton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,250
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920715

## Citation

> US National Institutes of Health, RePORTER application 9920715, A critical role for intracellular VEGF receptor translocation in ocular angiogenesis (5R01EY028861-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9920715. Licensed CC0.

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