New treatment targets found for blinding retinal disease

Date:
August 10, 2020
Source:
Medical College of Georgia at Augusta University
Summary:
When the eye isn't getting enough oxygen in the face of common
conditions like premature birth or diabetes, it sets in motion
a state of frenzied energy production that can ultimately result
in blindness, and now scientists have identified new points where
they may be able to calm the frenzy and instead enable recovery.



FULL STORY ==========================================================================
When the eye isn't getting enough oxygen in the face of common conditions
like premature birth or diabetes, it sets in motion a state of frenzied
energy production that can ultimately result in blindness, and now
scientists have identified new points where they may be able to calm
the frenzy and instead enable recovery.


==========================================================================
In this high-energy environ, both the endothelial cells that will form
new blood vessels in the retina -- which could improve oxygen levels --
and nearby microglia -- a type of macrophage that typically keeps watch
over the retina - - prefer glycolysis as a means to turn glucose into
their fuel.

Medical College of Georgia scientists have shown that in retinal disease,
the excessive byproducts of this inefficient fuel production system
initiate a crescendo of crosstalk between these two cell types. The talk promotes excessive inflammation and development of the classic mass
of leaky, dysfunctional capillaries that can obstruct vision and lead
to retinal detachment, says Dr. Yuqing Huo, director of the Vascular Inflammation Program at MCG's Vascular Biology Center.

The major byproduct of glycolysis is lactate, which also can be used as
a fuel, for example, by our muscles in a strenuous workout. Microglia
also need some lactate from the endothelial cells. But in disease,
the lactate is in definite oversupply, which instead supports this
destructive conversation between cells, says Huo, corresponding author
of the study in the journal Science Translational Medicine.

"This is a major problem in our country, loss of vision because of
compromised oxygen for a variety of reasons," says Dr. Zhiping Liu, postdoctoral fellow in Huo's lab and the study's first author. "We
hope this additional insight into how that process destroys vision,
will enable us to find better ways to intervene," Liu says.

In a low-oxygen environ, endothelial cells produce not only a lot of
lactate, but also factors that encourage nearby microglia to be more
active, and to use glycolysis to get more active, Huo says.



==========================================================================
In reality, microglia don't need the encouragement because they already
also seem to prefer this method of energy production. But the extra
lactate sent their way does spur them to produce even more energy and consequently even more lactate, Huo says.

The normally supportive immune cells also start overproducing
inflammation- promoting factors like cytokines and growth factors that
promote blood vessel growth or angiogenesis, which, in a vicious loop,
further turns up glycolysis by the endothelial cells, which are now
inclined to proliferate excessively.

"The reciprocal interaction between macrophages and (endothelial cells) promotes a feed-forward relationship that strongly augments angiogenesis,"
they write.

The destructive bottom line is termed pathological angiogenesis, a major
cause of irreversible blindness in people of all ages, the scientists say,
with problems like diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration.

"Our eyes clearly do not have sufficient oxygen, and they end up trying
to generate more blood vessels through this process called pathological angiogenesis, which is really hard to control," Huo says.



==========================================================================
The excessive sprouting and proliferation of endothelial cells is central
to the destruction, and glycolysis is central to their sprouting and proliferation but the exact mechanisms that trigger all the glycolysis
and crosstalk between endothelial cells and microglia have been unknown,
they write.

"In all these conditions, there is something wrong with the tissue that
causes the blood vessels to not behave properly," says coauthor Dr. Ruth
B. Caldwell, cell biologist in the Vascular Biology Center. "It's a bad
state," she says, which they want to help normalize.

As they are finding more about how the conversation goes bad between
these two cells, they are seeing new logical points to do that. When
they knock out the most potent activator of glycolysis, called Pfkfb3,
from the microglia, lactate production clearly goes down and the cells no longer aid production of dysfunctional capillaries. Conversely, expression
of both the messenger RNA that enables production of Pfkfb3 and lactate
are significantly higher in the cells when oxygen levels are low.

Agents that stop these cells' over-the-top use of glycolysis could be good therapeutic approaches, they say. Blocking excessive lactate production
could be another. Stopping the microglia from lapping up too much lactate
also significantly suppresses pathological angiogenesis in their lab
studies. Agents that normalize endothelial cell growth might work as well.

While genetic manipulation was used for much of their lab work to date,
the scientists are now looking at chemicals that might work at these
various points. A problem is that many drugs that suppress glycolysis
have numerous unwanted effects, so they are working to more selectively intervene. They note that since the use of glycolysis by macrophages is critical to support of a healthy immune response, localized inhibition
should yield the desired response without affecting the immune response.

Current treatments for abnormal blood vessel development and related
leaking and swelling include suppressing vascular endothelial growth
factor, or anti- VEGF, which, as the name implies, is a key factor
in endothelial cell growth, may require ongoing injections in the eye
and gets decent results in conditions like diabetic retinopathy. But
anti-VEGF therapy really does not facilitate repair, says Caldwell. The scientists have early evidence their intervention strategies may, because
they intervene earlier and help normalize the "bad" environment. "We
get repair and restoration," Caldwell says.

Huo and his colleagues are among those who have shown that glycolysis
is critical to the sprouting of endothelial cells and that mice lacking
Pfkfb3 have impaired angiogenesis.

Endothelial cells, which line all our blood vessels, are one of the
first things laid down when we make new blood vessels. In the retina,
they start making tiny tunnels that ideally will become well-functioning capillaries, blood vessels so small that a single red blood cell may
have to fold up just to get through. These thin-skinned blood vessels are
the point where oxygen, fluid and nutrients are provided to body tissue,
then blood gets routed back through the venous system to the heart where
the process starts anew.

Endothelial cells grow accustomed to glycolysis when they are helping
make our bodies in the early, no-oxygen days during development, Huo says.

The usual job of microglia includes keeping an eye out for invaders,
like a virus, and keeping connections between nerves, called synapses,
trimmed up.

Caldwell and Huo also are faculty members in the James and Jean Culver
Vision Discovery Institute at Augusta University and the MCG Department
of Cellular Biology and Anatomy.

The research was supported by the American Heart Association and the
National Institutes of Health.


========================================================================== Story Source: Materials provided by Medical_College_of_Georgia_at_Augusta_University. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Zhiping Liu, Jiean Xu, Qian Ma, Xiaoyu Zhang, Qiuhua Yang,
Lina Wang,
Yapeng Cao, Zhimin Xu, Amany Tawfik, Ye Sun, Neal L. Weintraub,
David J.

Fulton, Mei Hong, Zheng Dong, Lois E. H. Smith, Ruth B. Caldwell,
Akrit Sodhi, Yuqing Huo. Glycolysis links reciprocal activation
of myeloid cells and endothelial cells in the retinal angiogenic
niche. Science Translational Medicine, 2020; 12 (555): eaay1371 DOI:
10.1126/ scitranslmed.aay1371 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200810103255.htm

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