Brain Blood Flow Research Holds Promise for the Future

In the not-too-distant future we might see new developments in the treatment of stroke, Alzheimer's disease and other brain disorders, thanks to discoveries made about brain blood flow by researchers at Froedtert & The Medical College of Wisconsin. Scientists working under a five-year grant funded by the National Institutes of Health (NIH) have uncovered results that could have far-reaching effects for people who suffer from a variety of serious illnesses.

"This is a classic story. We have identified the gene that regulates brain blood flow, identified what that gene makes and identified what that substance does," said David Harder, PhD, Professor of Physiology and Director of the Cardiovascular Center at The Medical College of Wisconsin. Dr. Harder and his colleagues received the grant in 1999 for the purpose of expanding understanding of cerebral blood flow and the genetic mechanisms of its regulation.

The Research
Under Dr. Harder's direction, three projects were commenced under the grant:

• Project I was a detailed study of the gene's on-off switches. Defective switches which inhibit production of a substance that causes brain blood vessels to dilate, may play a role in many brain disorders, ranging from stroke and dementia to depression.
• Project II focused on the basic cellular and molecular mechanisms by which brain vessels sense environmental conditions.
• Project III involved how these mechanisms send signals to start or stop vessel contraction to dampen blood flow. Johns Hopkins researcher Richard Koehler, PhD was principal investigator for this project.

"We have done what we said we were going to do. The fact that we know what controls blood flow to the brain is important," Dr. Harder said. "We have finished our studies on animals and now it is time to begin studies on humans." As a result of Dr. Harder's and his colleagues' findings, the NIH has extended their grant for another five years. In the second five years of the study, the researchers will see how their results can be applied to people.

Understanding Brain Blood Flow
Brain blood flow is responsible for consistent nourishment to every brain cell, while sending extra flow to activate motor regions of the central nervous system on demand. "The gene that controls brain blood flow makes a substance that controls blood flow to the brain in response to neural activity. If neural activity increases, blood flow increases to support that activity. Say you move your arm. Those neurons that control that movement have to get extra blood," Dr. Harder explained.

Vessel contraction and dilation is a normal part of brain functioning, however, improperly regulated flow can result in brain disorders or damage such as blood clots or stroke. "In one project, we identified one of the mechanisms of cerebrovasospasm and reversed it in animals, but more study is necessary," Dr. Harder said.

Angiogenesis and Alzheimer's
You may have heard or read about the term angiogenesis - increase in the number of capillaries (small blood vessels) in certain parts of the body - in relation to growth of cancer tumors. Dr. Harder and his colleagues have discovered the role of astrocytes (cells found in the white matter of the brain that support other nerve cells) in promoting angiogenesis in the brain. This phenomenon is now considered a likely factor in the widely varying degrees of recovery seen after stroke or other brain injury.

"Some very serious diseases are affected by blood vessel growth. For example, we have found out that in patients with Alzheimer's disease, there are very few capillaries; they disappear. If we can induce growth of these vessels, perhaps we could change the course of the disease. This is just a hypothesis right now, but data suggests it may work so we are pursuing this idea," Dr. Harder said.

Another deadly condition called glioblastoma multiforme (GBM) is a very aggressive form of brain tumor. These tumors are affected by the presence of many capillaries in the brain. "Glioblastoma is a devastating disease that kills about one million children and young adults every year. It is a very vascular disease. If you can block that supply of blood, perhaps it could prevent the growth of the tumor," Dr. Harder said.

New Findings, New Medicines
Another of Dr. Harder's objectives was to find better modalities of prevention and treatment of cerebrovascular disease, such as stroke, blood clots and other diseases that affect the brain. Results of his studies indicate that new medicines may be on the way that will help scientists fight these deadly brain disorders.

In order to get the medicines to market, there must be a patent and a company to launch the medicines. "Cytometix is the new biomedical company we have set up to manufacture the compounds and obtain patents for them," he said. A company called TechStar is the initiative that will launch Cytometix.

"This is all very exciting news, but much more work has to be done. We are making plans to continue our studies," Dr. Harder said.

Dr. Harder's pioneering studies have revealed much of what is known today about the microcirculation of the brain. Most notably, he discovered a pivotal role for arachidonic acid, a brain chemical that is converted to substances that regulate blood vessel tone by a novel pathway.

Dr. Harder was elected to London's Royal Society of Medicine in 1987. He is an American Heart Association Clinical Fellow in Cardiology, a Fellow of its Council for High Blood Pressure research, and a Fellow of its Council on Circulation. Since 1982, his work has been funded by several prestigious national awards, including a five-year American Heart Association Established Investigator Award, a 10-year NIH Method to Extend Research in Time (MERIT) award, and a Research Career Scientist award from the US Veterans Administration.

JoAnn Petaschnick
HealthLink Contributing Writer

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.