Editorial

Hypoxic-Ischemic Encephalopathy: Impact on Retinal
Neurovascular Integrity and Function

Ismail S. Zaitoun1,2, PhD; Nader Sheibani1,2,3,4, PhD

1Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison,
WI, USA

2McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
3Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

4Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

ORCID:
Ismail Zaitoun: https://orcid.org/0000-0001-7174-5403

Nader Sheibani: https://orcid.org/0000-0003-2723-9217

J Ophthalmic Vis Res 2021; 16 (3): 317–319

Hypoxic-ischemic encephalopathy (HIE) along with
its impact on vision has been recognized for some
time. HIE, one of the most common brain injuries,
results from secondary oxygen deprivation and
blood flow reduction to the brain. Its incidence
ranges from 1 to 8 per 1,000 live births in
developed countries.[1] A considerable proportion
of HIE patients display visual impairment,[2, 3] which
was considered to be solely due to lesions in the
brain neural visual structures and processing.[4]
Although recent preclinical studies suggest a direct
impact on the retinal visual function, the underlying
mechanisms and the retinal cells targeted and
affected in response to HIE remain unknown.

The preclinical Rice-Vannucci model is a
frequently used acute HIE model in mouse and rat
pups.[5–9] This hypoxic-ischemic model is attained
by constant occlusion of only one of the common
carotid arteries (CCA) followed by exposure of the
animal to an air mixture with low oxygen. Exposure
to these conditions results in brain damage specific
to the hemisphere on the side of the ligated CCA.[10]
The CCA provides blood supply to the ophthalmic
artery that renders the eye susceptible to HIE
insult. This model is frequently used to study the
effect of HIE on structural and functional integrity
of the brain. In addition, this model has been used
to demonstrate the damaging effect of the HIE
on the blood vessels[11] or the neurons[12, 13] of the
rat retina. The development and homeostasis of
both the neuronal and the vascular systems are
interconnected.[14]

To the best of our knowledge, we were first to
report a detailed characterization of neurovascular

damage in the neonatal mouse retina after
exposure to Rice-Vannucci HIE model.[15] We
examined the effect of HI exposure of postnatal
day 9 (P9) neonatal mice on retinal neurovascular
integrity.[15] The mouse retina, like in the human, has
three layers of blood vessels. Our studies showed
that blood vessels in different layers were either
degenerated or failed to form. Similarly, our studies
demonstrated that exposure to HI conditions
induce neuronal degeneration and glial activation.
Observed vascular and neuronal damages were
irreversible and most noticeable in the periphery of
the retina.

Ischemic stroke can also occur in juvenile
humans and result in devastating and lasting
disabilities including vision loss. We recently
reported on the effect of HI exposure of juvenile
mice (age 30 days) on the functional and
structural integrity of the retinal blood vessels
and neurons.[16] These studies revealed that blood
vessels were damaged and that structural and
functional integrity of the neurons of the injured
retinas were affected as the b-wave and the inner
retinal layers were compromised.

Of note, we found retinal damage after exposure
to HI vary among individuals; some show mild to
no damage, some show moderate injuries, and
others show severe injuries. Similar interindividual
variabilities in the degree of damage after HIE
exposure were reported in mouse, rat, and human
neonatal brains[7, 17–19] and retina.[13, 20–22]

It is unknown why different individuals respond
differently after exposure to the same HI
conditions. Maturation status of blood vessels

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Hypoxic-Ischemic Encephalopathy; Zaitoun and Sheibani

and neurons could contribute to the severity of the
damage after exposure to ischemic stroke. This is
in line with the fact that we found the occurrence of
severe retinal vascular damage to be much higher
in neonates as compared with juvenile mice. Also,
the magnitude of the severe damage was far more
apparent and devastating in the neonate mice.
Thus, age seems to play a significant role. It is also
possible that variation in individual’s hemodynamic
properties could contribute to the HI-caused
damage,[23] since the vascular structure and hence
hemodynamic properties varies among retinas.
Also, retinas of male and female animals may show
different severity of injuries after exposure to the
same HI conditions, as in the brain.[24, 25]

Recent clinical studies have also demonstrated
that HIE results in direct retinal damage in
human neonates. At least 24.3% of eyes of
newborns with a history of HIE were found to
have retinal hemorrhage.[22, 26] An independent
study examined the retinal integrity of two infants
diagnosed with HIE using a handheld spectral
domain optical coherence tomography (SD-OCT)
imaging system. One infant with a history of
moderate HIE was found to have severe retinal
damage as manifested by thinning of all layers
of the retina. The second infant with a history of
severe HIE had subretinal fluid but without other
obvious retinal damage. These findings support
the notion that the retina is a prime target of
HI insult, and the severity of retinal damage is
independent of the severity of brain damage. A
more recent report found three out of eight (37.5%)
examined infants with HIE to have various types of
retinal damage, such as macular cystoid spaces,
thinning in the retinal ganglion cell layer, acute
middle maculopathy, and abnormally thin fovea.[20]

Preclinical studies including ours and recent
human reports demonstrate that both neurons
and blood vessels of the retina in neonates
and juveniles are vulnerable to HI exposure.
These findings call for more clinical attention in
assessing the structural and functional integrity
of retina of neonates and juvenile humans after
exposure to hypoxic-ischemic insults or ischemic
stroke. In addition, it is important to start effort
in developing interventional methods to prevent
and treat HI-induced and ischemic stroke-induced
retinal neurovascular damage. The underlying
mechanisms that lead to damage of neurons and
blood vessels in the retina after exposure to HI
conditions remain unknown.

The activation of cell death in brain begins
within the first 3–24 hr after exposure to HI

conditions.[27] It is likely that critical factors that are
responsible for the neurovascular degeneration
will be differentially expressed in the early stages
of the response to the HI insult. Single cell-RNA
sequencing (scRNA-Seq) method can be utilized
to determine changes in the transcriptome profiles
in the retina after the onset of the HI insult.
Identification of altered genes/pathways known to
be important for cell death, angiogenesis, and/or
neurogenesis could provide more details regarding
the underlying mechanisms. These pathways can
be targeted for development of new therapeutics
to preserve neurovascular functions not only in the
brain but also in the retina.

Financial Support and Sponsorship

This work was supported in part by an unrestricted
award from Research to Prevent Blindness to
the Department of Ophthalmology and Visual
Sciences; the Retina Research Foundation; NIH
grants P30 EY016665, P30 CA014520, S10
OD018221, and EY026078. NS is a recipient of
RPB Stein Innovation Award.

Conflicts of Interest

There is no conflict of interest.

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Correspondence to:

Ismail Zaitoun, PhD. Department of Ophthalmology and
Visual Sciences, University of Wisconsin School of
Medicine and Public Health, 1111 Highland Ave., WIMR
9418, Madison, WI 53705, USA.
E-mail: iszaitoun@wisc.edu
Received: 07-05-2021 Accepted: 01-06-2021

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DOI: 10.18502/jovr.v16i3.9427

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How to cite this article: Zaitoun IS, Sheibani N. Hypoxic-Ischemic
Encephalopathy: Impact on Retinal Neurovascular Integrity and Function. J
Ophthalmic Vis Res 2021;16:317–319.

JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 3, JULY-SEPTEMBER 2021 319

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