This shows blood vessels near the center of a healthy mouse retina --
arteries in green, veins in red.
Working with mice, Johns Hopkins
researchers have shed light on the activity of a protein pair found in cells
that form the walls of blood vessels in the brain and retina, experiments that
could lead to therapeutic control of the blood-brain barrier and of blood vessel
growth in the eye.
Their work reveals a dual role
for the protein pair, called Norrin/Frizzled-4, in managing the blood vessel
network that serves the brain and retina. The first job of the protein pair's
signaling is to form the network's proper 3-D architecture in the retina
during fetal development.
The second job, after birth, is to continue signaling to maintain the
blood-brain barrier, which gives the brain an extra layer of protection against
infection transmitted through the circulatory system.
The Hopkins researchers say
results of the study, published online in Cell on Dec. 7,
could have treatment implications for disorders of the retinal blood vessels
caused by diabetes, and age-related loss of central vision. They also could
help clinicians develop a way to temporarily increase the penetrability of the
blood-brain barrier, allowing critical drugs to pass through to the brain, says
Jeremy Nathans, M.D., Ph.D., a Howard Hughes researcher and professor of molecular biology and
genetics at the Institute for Basic Biomedical Sciences at the Johns Hopkins
School of Medicine.
Scientists already knew that
Frizzled-4 is a protein located on the surface of the cells that create blood vessel walls throughout
the body. Genetic
mutations that cause Frizzled-4's absence in mice and humans create
severe defects in blood
vessel development, but only in the retina, the light-absorbing sheet of
cells at the back of the eye. Retinal tissue consumes the most oxygen per gram
than any other tissue in the body. Therefore, three networked layers of blood
vessels are required to fulfill its oxygen needs. So blood vessel defects in
the retina generally starve it of oxygen, causing blindness.
In an effort to understand how
Frizzled-4 and its activator Norrin work normally, Nathans' team deleted Norrin
in mice. As a result, the rodents' retinal arteries and veins became confused
and crisscrossed.
Alternatively, if they turned
Norrin on earlier than usual, the networks began to develop earlier. And in
mice missing either Norrin or Frizzled-4, retinal blood vessels grew radially,
but they grew slowly and failed to create the second and third networked
layers. All of these results suggest that Norrin and Frizzled-4 play an
important role in the proper timing and arrangement of the retinal blood vessel
network, Nathans says.
The team also found that mice
missing just Frizzled-4, besides having major structural defects in their retinal blood vessels,
showed signs of a leaky blood-brain barrier and, similarly, a leaky
blood-retina barrier. To get at the cause of this, the team used special
genetic tricks to control the activity of Frizzled-4 in a time- and
cell-specific manner, creating mice that were missing Frizzled-4 in only about
one out of every 20 endothelial cells. What they found is that only the cells
missing Frizzled-4 were leaky and, surprisingly, the general architecture of
the networks was fine.
Nathans explains that, normally,
these blood vessel endothelial cells contain permeable "windows" and
relatively loose "bolts" connecting the cells together. When in the
brain and retina, they have no "windows" and their "bolts"
connect them tightly. Nathans adds, "We now know that endothelial cells
that make up the blood-brain barrier have to receive signals constantly from
nearby brain or retinal cells telling them, 'You're in the brain. Tighten your
bolts and close your windows.'"
The "windows" in the
other endothelial cells in the body are protein portals that allow large
molecules to pass through easily—to be filtered by the kidneys, for example.
The central nervous system, including the retina, is a privileged area. If toxins
were to pass through an endothelial "window" into the brain, the
resulting damage could be detrimental to the brain's activity. So the body
seals off these areas from bloodborne pathogens by tightening the
"bolts" between and closing the "windows" of the
endothelial cells that form the blood vessels servicing
those areas. This reinforcement of the endothelial cells is what is known as
the blood-brain barrier.
Although crucial to protecting
the central nervous system, the blood-brain barrier also prevents drugs in the
bloodstream from getting inside the brain to treat diseases, such as cancer.
"Our research shows that blood vessel cells lacking Frizzled-4 are leaky.
With this information in hand, we hope that someday it may be possible to
temporarily loosen the blood-brain barrier, allowing life-saving drugs to pass
through," says Nathans.
More information: dx.doi.org/10.1016… .2012.10.042
"Research on blood vessel
proteins holds promise for controlling 'blood-brain barrier'." December
6th, 2012. http://medicalxpress.com/news/2012-12-blood-vessel-proteins-blood-brain-barrier.html
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