# Promotion of retinal vascular hyperpermeability and macular edema by ANGPTL4

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $511,146

## Abstract

SUMMARY.
Ischemic retinopathies (IRs), the leading cause of severe vision impairment in working-age
Americans, remain a major public health concern. The recent introduction of therapies targeting
the hyper-permeability factor (HPF), vascular endothelial growth factor (VEGF), has had a
dramatic impact on the treatment of macular edema (ME) in patients with the two most common
IRs, diabetes and retinal vein occlusions (RVOs). However, clinical trials assessing the efficacy
of “anti-VEGF” therapies have demonstrated limited improvement in vision in almost half of these
patients despite treatment, underscoring the urgency to identify new, safe, and effective targets
for the treatment of ME in IR patients. In this regard, the landmark discovery of hypoxia-inducible
factor (HIF)-1α, a transcriptional enhancer that regulates the expression of hundreds of genes
(including VEGF) that adapt hypoxic cells and ischemic tissues to conditions of low oxygen
tension, has provided fundamental insight into the pathogenesis of IRs. Expression of HIF-1 is
increased in retinal Müller glial cells in the inner retina in IR animal models as well as in IR patients,
resulting in an increase in the expression of HIF-regulated genes. Nonetheless, several questions
remain unanswered: 1) Is VEGF the only HIF-regulated gene that plays a (significant) role in the
disruption of the integrity of the inner blood-retinal barrier (iBRB) and the promotion of ME in IR
patients (i.e., is VEGF the only good HIF-regulated target for the treatment of ME?) 2) If not, which
other HIF-regulated HPFs participate in the promotion of ME in IRs? 3) Are the expression levels
of these other HPFs higher in the eyes of IR patients who respond inadequately to anti-VEGF
therapies? 4) And finally, could targeting multiple factors be a more effective approach for the
treatment of ME in IRs? The research proposed here will address these fundamental gaps in our
knowledge. However, rather than confirming that known HPFs identified in other ischemic
diseases are also expressed in IRs, our lab has set out to identify and comprehensively examine
novel (understudied) HPFs that contribute to ME in these patients. Using an unbiased (agnostic)
approach, we have been the first to identify Angiopoietin-like 4 (ANGPTL4) as a potent HPF
upregulated by HIF in the hypoxic inner retina in IRs. This discovery could represent a paradigm
shift in our understanding of the pathogenesis of ME and is significant because it exposes a novel
therapeutic target for the treatment of ME in IR patients, including those who respond
inadequately to anti-VEGF therapy. The objective of this proposal is to interrogate the molecular
mechanisms by which ANGPTL4 promotes retinal vascular hyper-permeability with the final goal
of designing novel therapeutic drugs to treat ME.

## Key facts

- **NIH application ID:** 10006543
- **Project number:** 5R01EY025705-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** SILVIA V MONTANER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $511,146
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006543

## Citation

> US National Institutes of Health, RePORTER application 10006543, Promotion of retinal vascular hyperpermeability and macular edema by ANGPTL4 (5R01EY025705-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10006543. Licensed CC0.

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