Research on blood vessel proteins holds promise for controlling 'blood-brain barrier'

December 6, 2012
This shows blood vessels near the center of a healthy mouse retina -- arteries in green, veins in red. Credit: Yanshu Wang

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 . 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 .

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 . 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 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 throughout the body. that cause Frizzled-4's absence in mice and humans create severe defects in , 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 , 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 , 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 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 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.

Explore further: New molecular pathway regulating angiogenesis may fight retinal disease, cancers

More information: dx.doi.org/10.1016/j.cell.2012.10.042

Related Stories

Guiding light: how the brain gets wired for stereo vision

June 15, 2011

(Medical Xpress) -- Nerve cells that transmit light signals from the eye into the brain use a molecule best known for its role in blood vessel growth as a ‘stepping stone’ to help them reach the opposite brain hemisphere, ...

Recommended for you

New 'Tissue Velcro' could help repair damaged hearts

August 28, 2015

Engineers at the University of Toronto just made assembling functional heart tissue as easy as fastening your shoes. The team has created a biocompatible scaffold that allows sheets of beating heart cells to snap together ...

Fertilization discovery: Do sperm wield tiny harpoons?

August 26, 2015

Could the sperm harpoon the egg to facilitate fertilization? That's the intriguing possibility raised by the University of Virginia School of Medicine's discovery that a protein within the head of the sperm forms spiky filaments, ...

Research identifies protein that regulates body clock

August 26, 2015

New research into circadian rhythms by researchers at the University of Toronto Mississauga shows that the GRK2 protein plays a major role in regulating the body's internal clock and points the way to remedies for jet lag ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.