Related Experiment Video

Updated: Jul 16, 2025

Assessment of Vascular Regeneration in the CNS Using the Mouse Retina

Assessment of Vascular Regeneration in the CNS Using the Mouse Retina

Published on: June 23, 2014

Novel Function of Nogo-A as Negative Regulator of Endothelial Progenitor Cell Angiogenic Activity: Impact in

Pakiza Ruknudin¹, Ali Riza Nazari¹, Maelle Wirth^1,2

¹Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC H1T 2H2, Canada.

International Journal of Molecular Sciences

|September 9, 2023

Abstract:

Endothelial Progenitor Cells (EPCs) can actively participate in revascularization in oxygen-induced retinopathy (OIR). Yet the mechanisms responsible for their dysfunction is unclear. Nogo-A, whose function is traditionally related to the inhibition of neurite function in the central nervous system, has recently been documented to display anti-angiogenic pro-repellent properties. Based on the significant impact of EPCs in retinal vascularization, we surmised that Nogo-A affects EPC function, and proceeded to investigate the role of Nogo-A on EPC function in OIR. The expression of Nogo-A and its specific receptor NgR1 was significantly increased in isolated EPCs exposed to hyperoxia, as well as in EPCs isolated from rats subjected to OIR compared with respective controls (EPCs exposed to normoxia). EPCs exposed to hyperoxia displayed reduced migratory and tubulogenic activity, associated with the suppressed expression of prominent EPC-recruitment factors SDF-1/CXCR4. The inhibition of Nogo-A (using a Nogo-66 neutralizing antagonist peptide) or siRNA-NGR1 in hyperoxia-exposed EPCs restored SDF-1/CXCR4 expression and, in turn, rescued the curtailed neovascular functions of EPCs in hyperoxia. The in vivo intraperitoneal injection of engineered EPCs (Nogo-A-inhibited or NgR1-suppressed) in OIR rats at P5 (prior to exposure to hyperoxia) prevented retinal and choroidal vaso-obliteration upon localization adjacent to vasculature; coherently, the inhibition of Nogo-A/NgR1 in EPCs enhanced the expression of key angiogenic factors VEGF, SDF-1, PDGF, and EPO in retina; CXCR4 knock-down abrogated suppressed NgR1 pro-angiogenic effects. The findings revealed that hyperoxia-induced EPC malfunction is mediated to a significant extent by Nogo-A/NgR1 signaling via CXCR4 suppression; the inhibition of Nogo-A in EPCs restores specific angiogenic growth factors in retina and the ensuing vascularization of the retina in an OIR model.

Insights

Nogo-A signaling impairs endothelial progenitor cell (EPC) function in oxygen-induced retinopathy (OIR). Inhibiting Nogo-A restores EPCs

Area of Science:

Ophthalmology and Vascular Biology
Cell Biology and Neuroscience

Background:

Endothelial progenitor cells (EPCs) are crucial for revascularization in oxygen-induced retinopathy (OIR).
The mechanisms underlying EPC dysfunction in OIR, particularly the role of Nogo-A, are not fully understood.
Nogo-A, known for inhibiting neurite outgrowth, also exhibits anti-angiogenic properties.

Purpose of the Study:

To investigate the role of Nogo-A in EPC dysfunction within the context of OIR.
To explore the therapeutic potential of inhibiting Nogo-A signaling in OIR.

Main Methods:

Assessed Nogo-A and NgR1 expression in EPCs under hyperoxia and in an OIR rat model.
Evaluated EPC migratory and tubulogenic activities, and SDF-1/CXCR4 expression.
Utilized Nogo-A inhibition (peptide) and NgR1 suppression (siRNA) in vitro and in vivo (OIR rats).
Measured angiogenic factors (VEGF, SDF-1, PDGF, EPO) and assessed vascularization in OIR rat retinas.

Main Results:

Nogo-A and NgR1 expression increased in EPCs under hyperoxia and in OIR.
Hyperoxia-exposed EPCs showed reduced migration and tubulogenesis, linked to suppressed SDF-1/CXCR4.
Inhibition of Nogo-A/NgR1 restored SDF-1/CXCR4, rescued EPC function, and improved retinal vascularization in OIR rats.
Nogo-A/NgR1 inhibition upregulated key angiogenic factors in the retina.

Conclusions:

Hyperoxia-induced EPC dysfunction in OIR is significantly mediated by Nogo-A/NgR1 signaling via CXCR4 suppression.
Inhibiting Nogo-A in EPCs restores angiogenic potential and promotes retinal vascularization in an OIR model.
Targeting Nogo-A/NgR1 represents a promising therapeutic strategy for OIR.

Read full analysis

Keywords:

Endothelial Progenitor Cell (EPC)NgR1 Nogo-A angiogenesis oxygen-induced retinopathy (OIR)revascularization (RV)

More Related Videos

Oxygen-Induced Retinopathy Model for Ischemic Retinal Diseases in Rodents

Oxygen-Induced Retinopathy Model for Ischemic Retinal Diseases in Rodents

Published on: September 16, 2020

In Vitro Model of Coronary Angiogenesis

In Vitro Model of Coronary Angiogenesis

Published on: March 10, 2020

Related Concept Videos

Regulation of Angiogenesis and Blood Supply

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...

Mechanism of Angiogenesis

Mechanism of Angiogenesis

Blood vessel formation starts early during embryonic development, around day 7. In the extraembryonic yolk sac, mesodermal precursor cells called hemangioblast proliferate and differentiate into angioblast. Angioblasts express vascular endothelial growth factor receptor 2 or VEGFR2, which binds VEGF-A, a proangiogenic factor, guiding blood vessel formation. VEGF signaling promotes angioblasts to form a blood island in the developing embryo. Angioblasts further differentiate, giving rise to...

Nitric Oxide Signaling Pathway

Nitric Oxide Signaling Pathway

Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure...

Articles linked to this work by shared authors, journal, and citation graph.

Maternal and Postnatal Effects of Poly I:C-Induced Intrauterine Inflammation and Rytvela, a Non-Competitive IL-1R Antagonist, in the Pregnant Spiny Mouse.

Developmental neurobiology·2026

The long-term impact of retinopathy of prematurity on retinal function assessed with new patterns of mfERG analysis.

Documenta ophthalmologica. Advances in ophthalmology·2026

Inter- vs Intramolecular Aldehyde-Alkyne-Amine A3-Reaction in the Solution-Phase Synthesis of a Potent Macrocyclic Azapeptide CD36 Modulator.

The Journal of organic chemistry·2026

Disrupting the TGF-β-regulated epithelial-mesenchymal transition, apoptotic and autophagic phenotypes of 3D glioblastoma spheroids via glycolytic inhibition.

Exploration of targeted anti-tumor therapy·2026

Rytvela, an allosteric modulator of the interleukin-1 receptor, prevents preterm birth and neonatal complications in mice while nifedipine is ineffective.

Journal of immunology (Baltimore, Md. : 1950)·2026

Hypercholesterolemia Impairs the Expression of Angiogenic MicroRNAs in Extracellular Vesicles Within Ischemic Skeletal Muscles.

Non-coding RNA·2026

See all related articles