# Regulation of blood-retina barrier by placental growth factor

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2021 · $358,411

## Abstract

Project Summary
Diabetic retinopathy (DR) is a leading cause of vision loss and impairment worldwide. Diabetic macular edema
(DME) as a result of blood-retinal barrier (BRB) breakdown is a major complication of DR leading to blindness.
Despite the success of anti-vascular endothelial growth factor (VEGF) therapy on DME, little is known about
placental growth factor (PlGF)'s functional role in BRB breakdown in DR. PlGF, a member of the VEGF sub-
family, is a multifunctional cytokine with pathological angiogenic properties. Recent studies highlight PlGF's role
in BRB breakdown in DME. We recently showed that PlGF knockout (KO) mice were protected from diabetes-
caused BRB breakdown by upregulating several protective proteins. Emerging clinical studies showed that the
drug aflibercept, which blocks both PlGF and VEGF, prevented BRB breakdown in DME patients. Despite
these recent advances several questions remain to be addressed. 1) Is selective PlGF inhibition sufficient to
prevent diabetes-caused BRB breakdown? 2) What is the cell type-specific effect on BRB function by targeting
PlGF? 3) Does PlGF regulate BRB by mechanisms distinct from VEGF? 4) Are there interactions between
PlGF and VEGF (PlGF-VEGF heterodimers) that together contribute to BRB breakdown in DR? 5) What is the
role of VEGF receptor (VEGFR1) signaling in the regulation of human retinal endothelial cell (HREC) barrier
function? The answers to these important questions will better define PlGF's causal role in diabetes-induced
BRB breakdown that will lead to the design of better precision-targeted treatments for DME patients. Therefore,
the objective of this proposal is to address these questions. Our overall hypothesis is that targeting PlGF
prevents diabetes-caused BRB breakdown via upregulation of protective proteins, disruption of PlGF-VEGF
dimers, and inactivation of VEGFR1 in pericyte. Three specific aims are proposed to test the hypothesis. Aim-1
is to determine the role of key survival or antioxidant proteins in BRB protection by targeting PlGF in DR. Small
hairpin (sh) RNA and monoclonal antibody will silence or block PlGF in vivo or in vitro. The BRB protection by
survival or antioxidant proteins will be elucidated with HREC culture. Aim-2 is to determine the contribution of
PlGF-VEGF heterodimers on BRB breakdown in DR. PlGF KO mice will be used to determine if PlGF is
essential for DR-like features by VEGF. Insulin will treat diabetic mice to determine if hypoglycemia induces
PlGF-VEGF dimerization. A dominant-negative PlGF variant, which can heterodimerize with VEGF but not bind
VEGFR1, will determine the role of PlGF-VEGF in diabetes-induced BRB breakdown. Aim-3 is to determine the
role of VEGFR1 signaling in pericyte and its role in paracrine regulation of BRB function. The proposed
paracrine mechanism(s) will be deciphered: pericyte VEGFR1 signaling cascades triggered by high glucose
(HG) leads to upregulation of VEGF, PlGF, and/or VEGF-B expression and induction of V...

## Key facts

- **NIH application ID:** 10133079
- **Project number:** 5R01EY027824-05
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Hu Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,411
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133079

## Citation

> US National Institutes of Health, RePORTER application 10133079, Regulation of blood-retina barrier by placental growth factor (5R01EY027824-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133079. Licensed CC0.

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