Understanding the Tug-of-War Between Blood Vessel Constriction and Dilation

You run three miles on a treadmill. A technician installs equipment for the internet café on Mt. Everest at 16,000 feet. A heavily outfitted soldier swelters under the desert sun. A surgical team turns a patient on his side. A fit, trim and healthy octogenarian just can't exercise like she used to...

All of these scenarios interest Michael Joyner, M.D., a researcher in the Department of Anesthesiology and the vice chair of the Department of Physiology and Biomedical Engineering, because of the effects of the stresses of everyday life—exercise, altitude, heat, gravity and aging—on the mechanisms that control blood vessel dilation and contraction.

Who Pulls in the Tug-of-War Teams?

If you are healthy and your core temperature rises, either because of exercise or environmental stress, the blood flow to your skin increases to cool you down. When you exercise, blood flow to your muscle can increase by up to 100 times its regular rate. There are multiple substances, such as epinephrine, norepinephrine, angiotensin, and nitric oxide that interact to produce these results.

"It is thought that substances released by the muscle cause the blood vessels to dilate," explains Dr. Joyner. "But the sympathetic nerves also release substances that cause them to constrict. There's a constant tug-of-war between the multiple mechanisms that regulate the process."

The Human Integrative Physiology Laboratory, which Dr. Joyner co-directs, seeks to identify which factors are calling the shots in these, and other stress-initiated processes. The lab is particularly interested in understanding how aging, disease and genetic variation interfere with the normal process. They hope to apply what they learn to new therapies that will help healthy seniors and people with diabetes, hypertension, heat stroke and other heart, lung and blood diseases.

Dr. Joyner's lab recently earned international recognition for making a significant contribution to understanding this complex process.

The Nitric Oxide Debate

Two decades ago, scientists identified nitric oxide—a substance in the endothelial cells that line the blood vessels. In the late 1990s, the generally accepted thesis was that nitric oxide controlled the unknown mechanisms of the cardiovascular system. Dr. Joyner and Niki Dietz, M.D., an anesthesiologist who co-directs the Human Integrative Physiology Laboratory, focused their research on testing the thesis. In studies published from 1994 to 2000, their lab demonstrated that nitric oxide plays almost no role in some situations and only a minor role in others. More importantly, they discovered something new—that nitric oxide plays a significant role in the marked increase in blood flow that results from mental stress.

"For many years it was thought that special nerves acted to increase muscle blood flow during fight-or-flight responses," explains Dr. Joyner. "But our studies demonstrated that, in humans, the process is controlled by local effect that can be reversed by blocking nitric oxide."

Dr. Joyner concluded that nitric oxide is a natural buffering system that may be defective is some disease conditions.

"If nitric oxide is defective or insufficient, there is little control over rising blood pressure under conditions such as mental stress," explains Dr. Joyner. "And if the person already has hypertension (high blood pressure), their risk for coronary artery disease, congestive heart failure and stroke will be markedly increased."

Center for Translational Science Activities - Clinical Research Unit (CRU)

The outstanding facilities at Mayo Clinic's CTSA Clinical Research Unit (CRU) play a significant role in Dr. Joyner's ability to conduct highly controlled, invasive studies in humans—studies that seek to answer the tug-of-war questions. The CRU is an institutional resource that provides an optimal setting for controlled clinical studies, encourages collaboration among basic and clinical scientists, and serves as an excellent training environment for clinical investigators.

"Our ability to do basic science in humans is exceptional," says Dr. Joyner. "We are able to catheterize almost any blood vessel in the body and observe reactions to various stress situations. In addition, we can selectively infuse experimental drugs that either block the release of dilators or augment the release of constrictors. Then we can analyze the responses to each of them."

Dr. Joyner is energized by the close collaboration that the CRU encourages.

"It's a very exciting environment," says Dr. Joyner. "It's not at all unusual for cutting edge ideas to emerge from casual conversations in the hallways."

Collaboration Across the Disciplines

Dr. Joyner and his lab collaborate closely with investigators representing endocrinology, cardiovascular disease, hypertension, neurology, and molecular pharmacology and experimental therapeutics.

Diabetes

Robert Rizza, M.D., and Sreekumaran Nair, Ph.D., M.D., both endocrinologists, and physiologist Nisha Charkoudian are collaborating to discover why diabetes causes abnormalities in the blood vessels.

Dr. Nair studies the regulation of protein synthesis and degradation. Dr. Rizza is interested in how the treatment of diabetes with insulin is affected by changes in endothelial blood flow in the small vessels. And Dr. Charkoudian studies the role of autonomic nerves and other mechanisms that control skin circulation.

Diseases of the Nervous System

Dr. Joyner collaborates closely with neurologists Eduardo Benarroch, M.D., and Phillip Low, M.D., and W. Stephen Brimijoin, Ph.D., a molecular pharmacologist, on a NIH-funded Program Project to study autonomic nerve disorders. Diseases studied include diabetes, neurodegenerative disorders such as multiple system atrophy and Parkinson's disease, neuroimmunologic disorders, and postural tachycardia syndrome.

Lung Diseases

Bruce Johnson, Ph.D., a cardiovascular researcher, collaborates with Dr. Joyner in the Cardiovascular Health Clinic. Their studies explore alterations in the pulmonary system in chronic heart failure and how they influence exercise tolerance. Dr. Johnson conducts clinical trials in patients with chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF), to examine the influence of various interventions on cardiopulmonary response to exercise.

Genetic Variation that Affects Blood Flow

Some people have genes that program them for a greater response to one type of receptor—or that release more of one factor or another.

Dr. Joyner collaborates with Stephen Turner, M.D., a hypertension specialist, to identify genes that influence blood pressure and those that contribute to the development of coronary artery calcification. Better understanding of genetic differences will lead to a more accurate assessment for the risk of developing hypertension.

Michael Jensen, M.D., is an endocrinologist who is interested in research that could lead to new therapies that prevent obesity. His collaboration with Dr. Joyner has explored fuel metabolism during low- and high-intensity exercise. Their genetic variation studies seek to understand how genetic differences cause people to metabolize fat differently during exercise.

Bruce Johnson, Ph.D., a cardiovascular researcher, collaborates with Dr. Joyner in the Cardiovascular Health Clinic. Their studies examine how various genetic variations influence the cardiopulmonary responses to acute exercise.

Gene Therapy

In the future, Dr. Joyner looks forward to collaborating with Stephen Russell, M.D., Ph.D., program director of Mayo's Molecular Medicine Program.

"We're on the verge of being able to conduct gene therapy trials," says Dr. Joyner. "We have an extraordinary ability to phenotype the patient through Mayo's exceptional medical record system. And the CRU provides the infrastructure and the expertise necessary to conduct tightly controlled, safe human gene therapy trials."