The similarities between the pathways used by nerves and by blood vessels first struck anatomists hundreds of years ago; they appear clearly, for example, in the detailed drawings of Leonardo da Vinci. At the Society for Neuroscience meeting, researchers presented more than a dozen examples of neurovascular links in health and disease.
These connections suggest a common origin, research presented at SfN indicates; the signals first used by the nervous system were later “co-opted” and reused by the vascular system, Peter Carmeliet of the Flanders Interuniversity Institute for Biotechnology in Leuven, Belgium, said in a Presidential Special Lecture at the conference.
Unlike any other organ, the brain depends on continuous blood flow. If the circulation to a portion of the brain is interrupted, within seconds that area will lose its ability to function. A prolonged interruption—as, for example, with a stroke—can cause permanent damage.
Current research on stroke exemplifies the way scientific work on blood-brain interaction has developed during the past several decades. Thomas Jacobs, program director of the Neural Environment Cluster at the National Institute of Neurological Disorders and Stroke, said that research in the 1980s focused mainly on the vascular aspects of stroke and in the 1990s on the neuronal aspects, but these approaches yielded only one major new therapy, the “clot-busting” drug tPA.
Hence, at the turn of this century, scientists widened their focus to include not only neurons but also the blood vessels surrounding them and the structural cells, known as the glia, that hold them together. “Research on this emerging concept of a neurovascular unit is providing new leads toward understanding how the brain communicates with its blood vessels,” Jacobs said.
Focusing on a Growth Factor
At the center of attention is a chemical substance called vascular endothelial growth factor, or VEGF, which initiates the growth of new blood vessels. VEGF probably started out as a trigger for the growth of nerve fibers but has evolved into one of the most important substances in the formation and ongoing support of the circulatory system.
In a strain of mice that researchers bred to produce abnormally low levels of VEGF, blood vessels are often too thick or too thin, and tortuous instead of relatively straight. Each population of cells has its own proper levels of VEGF; an imbalance is now understood to lie at the root of more than 70 diseases. Too much VEGF can lead to cancer, inflammation, and diseases of the immune system; too little can bring on ischemic disease—that is, cell damage caused by the obstruction of blood flow—in the heart, brain, and many other tissues.
Costantino Iadecola, of Weill Medical College at Cornell University, points out that over the last decade it has become clear that the vascular system plays a role in certain diseases that have usually been considerered neurodegenerative, such as Alzheimer’s disease; for example, the notorious beta-amyloid peptide that builds up in the brain in Alzheimer’s has been found to disrupt the function of the cerebral blood vessels even before it begins to affect the neurons. Moreover, in a type of mouse developed as an animal model for Alzheimer’s disease, the failure of day-to-day maintenance of the blood vessels increases the animal’s susceptibility to ischemic injury.
In animals made vulnerable by low levels of VEGF, ischemia itself can also aggravate other ailments. One example comes from the mouse model of amyotrophic lateral sclerosis, or ALS, a degenerative disease of motor neurons that is rare but severely disabling and ultimately fatal in humans. In the mouse model, even a passing ischemic attack can worsen ALS.
Recent studies have implicated the gene responsible for VEGF in the degeneration of motor neurons. Researchers have identified three mutations of the VEGF gene that are associated with low levels of the growth factor and an increased risk of ALS; in addition, the cerebrospinal fluid of ALS patients has been found to contain abnormally low levels of VEGF.
Carmeliet and his colleagues have observed in mice bred to lack VEGF that cerebral blood flow is reduced even before the mice begin to develop neurodegenerative disease. Not surprisingly, these mice also appear unusually sensitive to transient ischemic attacks, or ministrokes, and then remain paralyzed longer than normal mice. Carmeliet proposes that inadequate levels of VEGF bring on the risk of disease in two ways: by inducing chronic ischemia and by causing or allowing motor neurons to degenerate.
Moreover, Carmeliet, his colleague Wim Robberecht, and their collaborators have found evidence that boosting the level of VEGF helps to protect against certain diseases. In the mouse model of ALS, not only does VEGF itself promote the survival of motor neurons under experimental stress, but VEGF gene therapy prolongs the animals’ survival. The growth factor that is produced stimulates motor neurons to sprout new axons and may also guard against the elimination of synapses.
The findings also indicate that VEGF protects motor neurons specifically where they are under threat; when the growth factor is delivered locally, it prevents damage to the neuromuscular junction, a critical step in the pathway from brain signal to muscle movement.
Delivering VEGF locally poses several challenges. The growth factor is composed of large molecules that cannot pass through the blood-brain barrier, a tight layer of cells in blood-vessel walls that prevents many substances in the bloodstream from entering the brain; it often provokes immune reactions; and it has a short half-life, which means the supply would continually have to be replenished.
For all these reasons, Carmeliet and his colleagues have developed a very small device that can hold recombinant VEGF and diffuse it through a permeable membrane directly into the ventricles, the fluid-filled cavities of the brain. The research team is now working toward clinical trials with the pharmaceutical company NeuroNova.
Gregory del Zoppo of the Scripps Research Institute pointed out that in order to be fully neuroprotective, a substance would have to protect not only the neurons but also other brain cells such as astrocytes and vascular cells. This multicellular consideration has slowed commercial development, although the long-term prospects remain good.
“Someone called this the Cinderella of neuroscience—she’s still scraping up the ashes,” del Zoppo said.
Astrocytes, important structural cells named for their starlike shape, are another possible neurovascular therapeutic target that have not yet received their due. Maiken Nedergaard of the University of Rochester said that astrocytes may be the most abundant cells in the human brain, outnumbering neurons by about 4 to 1 (in contrast, the ratio of astrocytes to neurons in rodents is 1 to 1, and in leeches, 1 astrocyte to 27 neurons). However, the greater complexity of the human astrocytes, which may make them more susceptible to dysfunction, imposes certain limits on the usefulness of animal models of brain disorders.
Another limiting factor in neurotherapeutic research is the blood-brain barrier itself, which can alter its permeability to bar some molecules from entering while allowing others through.
“The brain is the only organ that has such a barrier,” says William Pardridge of the University of California at Los Angeles. This unusual structure is necessary, he explains, because certain molecules that serve important functions throughout the body (such as norepinephrine, which increases heart rate and raises blood pressure) are put to use in a different capacity in the brain: as neurotransmitters.
There are also specialized transport systems to ferry essential small molecules, such as glucose, and even large ones, such as insulin, through the blood-brain barrier. Pardridge and his colleagues have devised a way to take advantage of one such system to deliver drugs to the brain, inside lipid spheres attached to monoclonal antibodies, which target specific molecules on the brain’s blood vessels.
Neurotransmitters that function elsewhere to regulate blood pressure and nerve pathways that later guide the mapping of blood vessels are but two glimpses into the intricate physiological partnerships that give us life from moment to moment. The interactions between the blood and the brain, in particular, invite closer study.
“These two fields should talk together quite a lot more than they do now,” Carmeliet said.