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Angiopoietin-1 is regulated by miR-204 and contributes to corneal neovascularization in KLEIP-deficient mice.
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Corneal
neovascularization
can
cause
loss
of
vision
.
The
introduction
of
anti-
VEGF
therapy
has
been
a
major
improvement
in
therapeutic
options
.
Recently
,
we
established
Kelch-like
Ect
2
-
interacting
protein
(
KLEIP
/
KLHL
20
)
knockout
mice
as
a
model
of
spontaneous
corneal
neovascular
dystrophy
.
The
aim
of
the
present
study
was
to
characterize
corneal
neovascularization
in
progressive
corneal
dystrophy
in
KLEIP
(
-
/
-
)
mice
,
to
evaluate
the
efficacy
of
anti-
VEGF
therapy
,
and
to
identify
novel
molecular
regulators
in
this
experimental
model
.
Corneal
neovascularization
was
assessed
by
immunohistochemistry
.
Vascular
endothelial
growth
factor
signaling
was
inhibited
by
injection
of
a
blocking
antibody
.
Microarrays
were
used
to
measure
expression
of
mRNA
and
microRNA
(
miRNA
)
in
dystrophic
corneae
.
Results
were
validated
by
immunohistochemistry
and
Western
blotting
.
Blood
vessels
and
lymphatics
grew
from
the
limbus
toward
the
dystrophic
epithelium
in
corneae
of
KLEIP
(
-
/
-
)
mice
.
Blocking
VEGF
signaling
did
not
reduce
phenotype
progression
.
Correspondingly
,
microarray
analysis
revealed
no
upregulation
of
canonical
vascular
growth
factors
in
late
dystrophy
.
During
phenotype
progression
,
angiopoietin-
1
expression
increased
while
miR-
204
expression
decreased
.
Bioinformatic
analysis
identified
a
binding
site
for
miR-
204
in
the
angiopoietin-
1
gene
.
Validation
by
in
vitro
experiments
confirmed
regulation
of
angiopoietin-
1
by
miR-
204
.
Vascular
endothelial
growth
factor
does
not
act
as
a
major
player
in
corneal
neovascularization
in
KLEIP
(
-
/
-
)
mice
.
However
,
the
proangiogenic
factor
angiopoietin-
1
was
strongly
upregulated
in
late
-
stage
phenotype
,
correlating
with
loss
of
miR-
204
expression
.
Correspondingly
,
we
identified
miR-
204
as
a
novel
regulator
of
angiopoietin-
1
in
vitro
.
These
findings
may
explain
the
incomplete
efficacy
of
anti-
VEGF
therapy
in
the
clinic
and
may
provide
new
candidates
for
pharmaceutical
intervention
.