Blood Vessel Protein Research Promising For Controlling ‘Blood-brain Barrier’

December 7, 2012
Image Caption: This shows blood vessels near the center of a healthy mouse retina -- arteries in green, veins in red. Credit: Yanshu Wang

Johns Hopkins Medicine

Experiments also suggest approaches to treating blood vessel disorders 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.



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.


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.

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Source: Johns Hopkins Medicine

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