A walk-on to the University of Arizona men’s track and cross country teams in 1977, Michael Joyner, M.D., a Co-Principal Investigator of Mayo’s Center for Translational Sciences Activities (CTSA), fell victim to a “terrible, classic case of 19-year-old male syndrome. School was devoid of meaning. I seriously thought of dropping out and joining Tucson’s fire department.”

Enthusiasm for an entirely different career was sparked after a race when graduate student, Eddie Coyle (later the physiologist who studied Lance Armstrong) asked Dr. Joyner to volunteer to be studied in a physiology experiment to predict distance running performance by measuring blood lactate levels.

“This whole world opened up to me,” says Dr. Joyner. “I had a focus, became a much better student, and began volunteering at the laboratory.”

The common thread of Dr. Joyner’s subsequent research is how the body, especially the cardiovascular system, responds to physical and mental stresses. His focus is the autonomic nervous system, which is not consciously controlled and regulates blood pressure, breathing, body temperature and heart rate.

Sex differences in blood pressure regulation

In studies to determine differences between the way men and women regulate blood pressure, Dr. Joyner collaborates with fellow Mayo physiologist Nisha Charkoudian, Ph.D. and Swedish scientist, Dr. Gunnar Wallin, who helped pioneer the microneurography technique with which researchers can directly measure the activity of sympathetic nerves in humans.

The group is particularly interested in discovering why people with high sympathetic nerve activity do not have high blood pressure. Sympathetic nerves control the caliber of blood vessels and play a major role in the regulation of blood pressure. The activity of sympathetic nerves in people with normal blood pressure can vary five or 10-fold.

Led by Emma Hart, Ph.D., a research fellow in Dr. Joyner’s lab, the research team’s latest study reveals a difference in how nerve traffic (nerve pulses per minute) influences the way men and women regulate blood pressure (Hypertension Mar 2009). The findings may have important implications for understanding how hypertension and other disorders of blood pressure regulation occur in men and women.

“We took some young men with variable nerve traffic and showed that people with very high nerve traffic had constricted blood vessels but a lower cardiac output, and that was one of the factors that kept them from having high blood pressure,” says Dr. Joyner. In young women this relationship was absent. “It’s an indication that the women’s blood vessels and cardiovascular systems responded to nerve impulses differently.”

In young women, the team suspects that reproductive hormones, known to be protective against cardiovascular disease, may prevent the blood vessels from becoming constricted when nerve traffic is high.

“We've known for many years that men and women are different in terms of blood pressure regulation,” says Dr. Charkoudian. “We know that young women have a lower risk of developing hypertension (high blood pressure) compared to young men. In this study, we focused on the importance of the sympathetic nervous system and its control of blood vessels as determinants of long-term blood pressure. Our data suggest that one of the ways women are ‘protected’ is by an influence of female hormones to alter this nerve-blood vessel interaction.”

The Joyner lab recruits a wide range of people for their studies including the occasional elite or master athlete, active and sedentary people, and those with medical conditions such as hypertension, heart failure, diseases of the autonomic nervous system and, especially people who have problems with blood pressure regulation. Another collaborator, Philip Low, M.D. is a Mayo neurologist and a pioneer in research of diseases that cause low blood pressure.

Contracting muscles and blood flow

Dr. Joyner is also exploring what factors increase blood flow to exercising muscles. The flow of blood to a muscle during exercise can increase about 100-fold.

“That’s not 100 percent, but 100 times!” emphasizes Dr. Joyner. “The factors that make this possible are not well understood, even though this was first described in the 1870s. Another fundamental puzzle is what makes a person’s skin blood flow go up when they get hot. What makes us breathe faster when exercising is not that well known either.

“For people to have optimal health they have to be able to regulate temperature and breathing during exercise, so it’s important that blood flow to their muscles goes up. If not, you have limited exercise tolerance, and as a result all sorts of bad things can happen.”

Another study designed to understand what makes blood flow to exercising muscle increase examines how skeletal muscles respond to a reduction of oxygen delivery, either from hypoxia (low oxygen concentration in the blood) or from reduced blood flow caused by mechanical obstruction. To study this, Dr. Joyner gives subjects gas mixtures “that makes it seem like they’re at Pike’s Peak.”

The effect of mental and physiological stresses

Anesthesiologist and Joyner team member, John Eisenach, M.D., focuses his research on understanding responses to mental and physiological stresses and the role of genetics in blood pressure regulation.

A large group of subjects has been recruited to study why some people are blood pressure responders while others are non-responders to mental stress. People who are responders have big blood pressure spikes and are at risk for high blood pressure. In response to challenging arithmetic and word tests, some volunteers have a 10-millimeter rise in blood pressure, while others go up 40 mm.

“As human integrative physiologists, one of our scientific contributions is to bridge functional genomic discoveries with actual physiologic traits in humans,” says Dr. Eisenach. “We would like to know how genetic variation in a major heart and blood vessel receptor (the beta-2 adrenergic receptor) influences cardiovascular regulation.”

The lab groups healthy young adult volunteers according to diverse, yet commonly inherited forms of the beta-2 receptor. They then test response to stressful maneuvers, medication infusions, and dietary sodium intake.

“Results suggest that gene variation in the receptor affects the cardiovascular response to medication infusions and laboratory stress maneuvers,” says Dr. Eisenach. “We have also found that dietary sodium influences the functional properties of these gene variants. We are now determining whether a high salt diet accentuates the gene-dependent differences in receptor function.”

Blood flow in Alzheimer’s disease

In collaboration with Mayo’s Alzheimer’s Disease Research Center Dr. Joyner and vascular biologist Zvonimir Katusic, M.D, Ph.D., are beginning studies to understand how brain blood flow and blood vessel health relates to cognition in the brains of older people at risk for cognitive impairment and Alzheimer’s disease. Dr. Joyner’s team will perform physiological tests on the patients while Dr. Katusic will study a subclass of blood cells called endothelial progenitor cells.

“These cells are at some level your own personal stem cells,” Dr. Joyner explains. “If you have healthy ones there are indications that they help repair the body so you don’t age as rapidly. Bad ones could indicate a limited ability to repair things when they go wrong.”

The Alzheimer collaboration is illustrative of how research is conducted at the Mayo Clinic, Dr. Joyner says.

“Here’s a study that includes researchers interested in populations, to one like me interested in individuals, to people like Zvonimir interested in cells from individuals,” he says. “Working at Mayo is the ultimate team sport.”

— Tony Fitzpatrick, May 2009