Research on blood vessel proteins holds promise for controlling 'blood-brain barrier'
December 6, 2012 in Medical research
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 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
Journal reference:
Cell
Provided by
Johns Hopkins University School of Medicine
-
Sight gone, but not necessarily lost? Researchers find life in blood-starved retinas
Oct 30, 2009 |
not rated yet |
0
-
Researchers find a new culprit in Alzheimer's disease: Too many blood vessels
Aug 31, 2011 |
not rated yet |
0
-
Stem cells used to create critical brain barrier in lab
Dec 20, 2006 |
not rated yet |
0
-
Guiding light: how the brain gets wired for stereo vision
Jun 15, 2011 |
not rated yet |
0
-
New molecular pathway regulating angiogenesis may fight retinal disease, cancers
May 29, 2011 |
not rated yet |
0
-
Motion perception revisited: High Phi effect challenges established motion perception assumptions
Apr 23, 2013 |
3 / 5 (2) |
2
-
Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update)
Apr 02, 2013 |
4.5 / 5 (11) |
5
-
The visual system as economist: Neural resource allocation in visual adaptation
Mar 30, 2013 |
5 / 5 (2) |
9
-
Separate lives: Neuronal and organismal lifespans decoupled
Mar 27, 2013 |
4.9 / 5 (8) |
0
-
Sizing things up: The evolutionary neurobiology of scale invariance
Feb 28, 2013 |
4.8 / 5 (10) |
14
-
If you became brain-dead, would you want them to pull the plug?
15 hours ago
-
MRI bill question
May 15, 2013
-
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013
-
Alcohol and acetaminophen
May 13, 2013
-
Marie Curie's leukemia
May 13, 2013
-
Genetic variations within and between populations
May 12, 2013
- More from Physics Forums - Medical Sciences
More news stories
Now we know why old scizophrenia medicine works on antibiotics-resistant bacteria
In 2008 researchers from the University of Southern Denmark showed that the drug thioridazine, which has previously been used to treat schizophrenia, is also a powerful weapon against antibiotic-resistant bacteria such as ...
Medical research
9 hours ago |
3.7 / 5 (3) |
0
|
SUMO wrestling cells reveal new protective mechanism target for stroke
Scientists investigating the interaction of a group of proteins in the brain responsible for protecting nerve cells from damage have identified a new target that could increase cell survival.
Medical research
15 hours ago |
5 / 5 (1) |
0
How serotonin receptors can shape drug effects, from LSD to migraine medication
New findings by researchers carrying out experiments at the U.S. Department of Energy Office of Science's Advanced Photon Source (APS) help explain why some drugs that interact with two kinds of human serotonin ...
Medical research
17 hours ago |
not rated yet |
0
|
Preventing blood poisoning
Peptide molecules derived from the body's natural immune system can help boost the body's defence against life-threatening blood poisoning, joint University research has uncovered.
Medical research
17 hours ago |
4 / 5 (1) |
0
|
New mechanism to prevent type 2 diabetes in obese individuals
A new Montréal study conducted by Dr. May Faraj, associate research professor at the Université de Montréal and invited scientist at the IRCM, along with her research team and medical collaborators, shows ...
Medical research
17 hours ago |
not rated yet |
0
|
AIDS science at 30: 'Cure' now part of lexicon
Big names in medicine are set to give an upbeat assessment of the war on AIDS on Tuesday, 30 years after French researchers identified the virus that causes the disease.
For combat veterans suffering from post-traumatic stress disorder, 'fear circuitry' in the brain never rests
Chronic trauma can inflict lasting damage to brain regions associated with fear and anxiety. Previous imaging studies of people with post-traumatic stress disorder, or PTSD, have shown that these brain regions can over-or ...
Flesh-eating disease victim gets prosthetic hands
(AP)—A woman who lost both hands, her left leg and right foot after contracting a flesh-eating disease has been fitted with prosthetic hands.
Temporal processing in the olfactory system
The neural machinery underlying our olfactory sense continues to be an enigma for neuroscience. A recent review in Neuron seeks to expand traditional ideas about how neurons in the olfactory bulb might encode information about ...
Melon focus headband turns to Kickstarter for rollout plans
(Medical Xpress)—What if the quality of your work depends more on your focus on the piano keys or canvas or laptop than your musical or painting or computing skills? If target users can be convinced, they ...
College women exceed NIAAA drinking guidelines more frequently than college men
In order to avoid harms associated with alcohol consumption, in 2009 the National Institute on Alcohol Abuse and Alcoholism issued guidelines that define low-risk drinking. These guidelines differ for men and women: no more ...