# Investigating the role of mitochondrial dysfunction in the pathogenesis of retinal vascular diseases

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $418,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Angiogenesis is the process of blood vessel formation in which proliferating endothelial cells (ECs) sprout from
preexisting vessels to extend a vascular network. Either impaired or excessive angiogenesis is associated with
the pathogenesis of human retina diseases such as retinal hypovascular familial exudative vitreoretinopathy and
hypervascular diabetic retinopathy. EC primarily uses the glycolysis pathway which is further enhanced during
angiogenesis. Recent studies suggest that mitochondrial activity is critical for angiogenesis, but its mechanism
is not entirely clear. We have investigated the angiogenic functions of three mitochondrial proteins with distinct
activities - mitochondrial transcriptional factor (TFAM), respiratory complex IV component (COX10) and a
mitochondrial redox protein thioredoxin 2 (TRX2). Our data show that: 1) silencing of Tfam, Cox10, or Trx2 in an
in vitro 3D sprouting assay attenuates EC sprouting, which correlated with reduced EC proliferation, but not with
ROS generation or EC apoptosis; 2) mice with an inducible deletion of Tfam, Cox10, or Trx2 exhibit retarded
retinal vessel growth without penetration into the deep plexi at early ages (P5–P12), and this attenuated retinal
sprouting was not correlated with mtROS production; 3) the three mutant mice develop arteriovenous
malformations (AVM) with enhanced arterialization and microaneurysm formation in the microvessels at
advanced ages (P12–P30). The hypovasculature and microaneurysm phenotypes resemble that of aged human
retinas and human retinal vascular abnormalities such as Coats' disease, Leber's military aneurysms and familial
exudative vitreoretinopathy (FEVR); 4) Furthermore, single-cell RNA-seq analyses of retinal ECs suggest that
the three mutant mice have common EC clusters with reduced gene expression in angiogenic and metabolic
pathways but increased TGFR signaling. Based on these data, we hypothesize that mitochondrial activity
regulates common angiogenic and metabolic pathways (rather than ROS/apoptosis) in vascular growth and
maturation. We propose the following specific aims: 1) To identify critical angiogenic and metabolic pathways
in mitochondrial dysfunction-induced defects in retinal sprouting angiogenesis, AVM and microaneurysm
formation as well as in retinal function; 2) To define how mitochondrial dysfunction regulates TGFR-Smad2/3
signaling; 3) To determine the role of the TGFR-Smad2/3 signaling in mitochondrial dysfunction-induced
vascular retardation and malformation by pharmacological blockade and genetic deficiency. Our proposed study
will define the mechanism by which mitochondrial activities regulate normal retinal vascular growth and
maturation, and will provide a novel model and therapeutic intervention for human retinal vascular diseases
associated with many pathological complications such as diabetes, hypertension and aging that can result in
vision loss.
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## Key facts

- **NIH application ID:** 10443059
- **Project number:** 1R01EY033333-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jenny Huanjiao Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,750
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443059

## Citation

> US National Institutes of Health, RePORTER application 10443059, Investigating the role of mitochondrial dysfunction in the pathogenesis of retinal vascular diseases (1R01EY033333-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10443059. Licensed CC0.

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