Fast blood flow protects against atherosclerosis: implications for treatment

Graphic: Andrew Swift

By Christina M. Warboys, Narges Amini, Amalia de Luca, and Paul C. Evans, February 8, 2011  —  Despite recent advances in this field, the influence of shear stress on vascular physiology remains poorly understood. Broader gene-expression profiling studies of endothelial cells at atherosusceptible and protected sites are now required to further define the molecular mechanisms that control the spatial distribution of inflammation and plaque formation, with the hope of uncovering other targets for pharmacological manipulation.  Findings also suggest that consumption of sulforaphane-rich vegetables may lower the risk of atherosclerosis.

The formation of atherosclerotic plaques within arteries underlies most forms of cardiovascular disease (CVD). Atherosclerosis is a chronic inflammatory disease in which inflammatory cells (e.g. leukocytes) and lipids accumulate to form a plaque within the artery wall, underneath the endothelial cells which line the vessel. Despite a wide range of systemically acting risk factors, such as high cholesterol, plaques are not distributed evenly throughout blood vessels. Plaques tend to form in regions of the arterial tree where there are bends or where the vessels fork into branches. In 1969, Colin Caro and colleagues made the observation that these areas of plaque formation were associated with low or altered blood flow.1 This led to the idea that mechanical forces might play a role in lesion development. In recent years researchers have started to investigate and understand the molecular mechanisms underlying plaque formation, bringing Caro’s findings into sharp relief.

The endothelium is in direct contact with blood and is therefore constantly exposed to the drag force exerted by flowing blood, known as shear stress. Regions of vessel curvature or branch points, experience low and/or disturbed blood flow, creating an area of low shear stress. Straight, unbranching vessels experience uniform, unidirectional flow, creating high shear stress—which protects vessels from plaque formation. In 2005, Martin Schwartz and colleagues identified a mechanosensory complex on endothelial cells which was able to detect mechanical forces exerted by the flowing blood and initiate signalling within the cell that resulted in changes in endothelial cell function.

Endothelial cells in regions of disturbed blood flow have been found to exhibit low-grade chronic inflammation and have differential expression of a number of genes implicated in both the inflammatory response and in protection against it, suggesting that shear stress may influence the inflammatory state of the endothelium. In the last decade, researchers have begun to trace the pathways by which that influence might operate.

The infiltration of inflammatory leukocytes into the vessel wall occurs very early in cardiovascular disease, and is considered a key factor in the development of atherosclerosis. Leukocyte infiltration is triggered by proinflammatory signalling from the endothelium, which increases the expression of adhesion molecules such as VCAM-1 and E-selectin, thus causing leukocyte recruitment. Two key proinflammatory signalling pathways, the mitogen- activated protein kinase (MAPK) pathway and nuclear factor-κB (NF-κB) pathway, have been identified as being differentially regulated at protected and susceptible sites of the arterial tree.

Endothelial cells at low-shear regions are primed for NF-κB signaling, whereas NF-κB activity in high-shear regions is minimal. This has been attributed to the expression of a key negative regulator of NF-κB signaling, Krüppel-like factor 2 (KLF2) in protected areas, which sequesters a critical coactivator of NF-κB, preventing transcription. Numerous studies have shown that KLF2 is activated in response to high shear stress, placing KLF2 as a key mediator of the anti-inflammatory effects of high shear stress. The atheroprotective effects of KLF2 may also be attributed to negative regulation of the proinflammatory MAPK network, since KLF2 inhibits the nuclear localization of MAPK transcription factors.

To read more: go to When Stress Is Good – The Scientist – Magazine of the Life Sciences

PUSHING IT: Stress is linked indirectly to the immune system’s anti-tumor
defenses, but it can also affect anoikis–a type of cell death that cancer cells bypass. Image: iStockphoto

A new study shows stress hormones make it easier for malignant tumors to grow and spread, by Katie Moisse —  A little stress can do us good—it pushes us to compete and innovate. But chronic stress can increase the risk of diseases such as depression, heart disease and even cancer. Studies have shown that stress might promote cancer indirectly by weakening the immune system’s anti-tumor defense or by encouraging new tumor-feeding blood vessels to form. But a new study published April 12 in The Journal of Clinical Investigation shows that stress hormones, such as adrenaline, can directly support tumor growth and spread.

For normal cells to thrive in the body, “they need to be attached to their neighbors and their surroundings,” says the study’s lead author Anil Sood from The University of Texas M. D, Anderson Cancer Center in Houston. Cells that detach from their environment undergo a form of programmed cell death called anoikis. “But cancer cells have come up with way to bypass this effect—they avoid anoikis,” Sood says. This allows cancer cells to break off from tumors, spread throughout the body (in blood or other fluid) and form new tumors at distant sites—a process called metastasis. So Sood wondered: Could stress affect anoikis? “It surprised us that this biology hadn’t been studied before,” he notes. “Stress influences so many normal physiological processes. Why wouldn’t it be involved in tumor progression?”

Sood and his team first studied the effects of stress hormones on human ovarian cancer cell anoikis in culture. Cells that were exposed to stress hormones were protected from self destruction—meaning they could survive without being anchored to their surroundings. The stress hormone treatment activated a protein called FAK (focal adhesion kinase), which is known to protect cells from anoikis. Inhibiting FAK reversed the effects.

But real tumors behave differently than cancer cells in vitro, so Sood and his team extended their exciting findings into a mouse model of cancer. After receiving a transplant of ovarian cancer cells, mice were restrained to cause stress. As such, their tumors grow more quickly. Isoproterenol (a drug similar to adrenaline) had the same accelerative effect. The tumor-feeding effects of behaviorally and pharmacologically induced stress, both of which were mediated by FAK, were inhibited by the adrenaline-blocking drug propranolol.

But how closely does the stress caused by restraining a lab animal mimic that experienced by human patients? Sood and colleagues looked at samples from 80 cases of human ovarian cancer grouped according to patient stress using the National Institutes of Health’s Center for Epidemiological Studies Depression scale as a surrogate marker. Patient stress (according to the scale), along with elevated stress hormone activity were associated with higher levels of activated FAK, which was in turn linked to faster disease progression.

Ovaries contain high levels of stress hormones compared with other organs, but Sood plans to investigate whether the stressors could still be involved in other types of cancer. He hopes to identify ways to interfere with the tumor-feeding effects of stress hormones either behaviorally or pharmacologically. “Reducing the hormone levels may not be so easy,” Sood says. “Blocking the receptors using drugs like beta-blockers or antidepressants may be a better strategy.” Teaching patients to manage their stress using cognitive behavioral therapy might also be effective, he adds. “We’re really trying to understand the biology. We hope it will help us identify better therapeutic strategies.”

National Cancer Institute


The complex relationship between physical and psychological health is not well understood. Scientists know that psychological stress can affect the immune system, the body’s defense against infection and disease (including cancer); however, it is not yet known whether stress increases a person’s susceptibility to disease (1).

1.       What is psychological stress?

Psychological stress refers to the emotional and physiological reactions experienced when an individual confronts a situation in which the demands go beyond their coping resources. Examples of stressful situations are marital problems, death of a loved one, abuse, health problems, and financial crises (2).

2.       How does stress affect the body?

The body responds to stress by releasing stress hormones, such as epinephrine (also called adrenaline) and cortisol (also called hydrocortisone). The body produces these stress hormones to help a person react to a situation with more speed and strength. Stress hormones increase blood pressure, heart rate, and blood sugar levels. Small amounts of stress are believed to be beneficial, but chronic (persisting or progressing over a long period of time) high levels of stress are thought to be harmful (1).

Stress that is chronic can increase the risk of obesity, heart disease, depression, and various other illnesses. Stress also can lead to unhealthy behaviors, such as overeating, smoking, or abusing drugs or alcohol, that may affect cancer risk.

3.       Can stress increase a person’s risk of developing cancer?

Studies done over the past 30 years that examined the relationship between psychological factors, including stress, and cancer risk have produced conflicting results. Although the results of some studies have indicated a link between various psychological factors and an increased risk of developing cancer, a direct cause-and-effect relationship has not been proven (3, 4).

Some studies have indicated an indirect relationship between stress and certain types of virus-related tumors. Evidence from both animal and human studies suggests that chronic stress weakens a person’s immune system, which in turn may affect the incidence of virus-associated cancers, such as Kaposi sarcoma and some lymphomas (5).

More recent research with animal models (animals with a disease that is similar to or the same as a disease in humans) suggests that the body’s neuroendocrine response (release of hormones into the blood in response to stimulation of the nervous system) can directly alter important processes in cells that help protect against the formation of cancer, such as DNA repair and the regulation of cell growth (6).

4.       Why are the study results inconsistent?

It is difficult to separate stress from other physical or emotional factors when examining cancer risk (3, 4). For example, certain behaviors, such as smoking and using alcohol, and biological factors, such as growing older, becoming overweight, and having a family history of cancer, are common risk factors for cancer. Researchers may have difficulty controlling the presence of these factors in the study group or separating the effects of stress from the effects of these other factors (3). In some cases, the number of people in the study, length of follow-up, or analysis used is insufficient to rule out the role of chance (4). Also, studies may not always take into account that cancer is not a homogeneous (uniform in nature) disease.

5.       How does stress affect people who have cancer?

Studies have indicated that stress can affect tumor growth and spread, but the precise biological mechanisms underlying these effects are not well understood. Scientists have suggested that the effects of stress on the immune system may in turn affect the growth of some tumors (7). However, recent research using animal models indicates that the body’s release of stress hormones can affect cancer cell functions directly (8).

A review of studies that evaluated psychological factors and outcome in cancer patients suggests an association between certain psychological factors, such as feeling helpless or suppressing negative emotions, and the growth or spread of cancer, although this relationship was not consistently seen in all studies (3). In general, stronger relationships have been found between psychological factors and cancer growth and spread than between psychological factors and cancer development (6).

6.       Where can a person find more information about psychological stress?

Additional information about stress can be found on the National Institute of Mental Health’s (NIMH) Web site at on the Internet. The NIMH, a part of the National Institutes of Health, provides national leadership in the study of mental and behavioral disorders, including the causes and effects of psychological stress.

The National Women’s Health Information Center (NWHIC), a service of the Office on Women’s Health, provides information on stress and health on its Web site at on the Internet. In particular, the fact sheet Stress and Your Health provides answers to frequently asked questions about causes of stress, how women react to stress, and ways to handle stress. This resource is available at on the Internet.

A beautiful genius of an idea…..

The New York Times, February 7, 2011, by Patricia Leigh Brown, VALLEY CENTER, Calif. — On an organic farm here in avocado country, a group of young Marines, veterans and Army reservists listened intently to an old hand from the front lines.

“Think of it in military terms,” he told the young recruits, some just back from Iraq or Afghanistan. “It’s a matter of survival, an uphill battle. You have to think everything is against you and hope to stay alive.”

The battle in question was not the typical ground assault, but organic farming — how to identify beneficial insects, for instance, or to prevent stray frogs from clogging an irrigation system. It was Day 2 of a novel boot camp for veterans and active-duty military personnel, including Marines from nearby Camp Pendleton, who might be interested in new careers as farmers.

“In the military, grunts are the guys who get dirty, do the work and are generally underappreciated,” said Colin Archipley, a decorated Marine Corps infantry sergeant turned organic farmer, who developed the program with his wife, Karen, after his three tours in Iraq. “I think farmers are the same.”

At their farm, called Archi’s Acres, the sound of crickets and croaking frogs communes with the drone of choppers. The syllabus, approved by Camp Pendleton’s transition assistance program, includes hands-on planting and irrigating, lectures about “high-value niche markets” and production of a business plan that is assessed by food professionals and business professors.

Along with Combat Boots to Cowboy Boots, a new program for veterans at the University of Nebraska’s College of Technical Agriculture, and farming fellowships for wounded soldiers, the six-week course offered here is part of a nascent “veteran-centric” farming movement. Its goal is to bring the energy of young soldiers re-entering civilian life to the aging farm population of rural America. Half of all farmers are likely to retire in the next decade, according to the Agriculture Department.

“The military is not for the faint of heart, and farming isn’t either,” said Michael O’Gorman, an organic farmer who founded the nonprofit Farmer-Veteran Coalition, which supports sustainable-agriculture training. “There are eight times as many farmers over age 65 as under. There is a tremendous need for young farmers, and a big wave of young people inspired to go into the service who are coming home.”

About 45 percent of the military comes from rural communities, compared with one-sixth of the total population, according to the Carsey Institute at the University of New Hampshire. In 2009, the Agriculture Department began offering low-interest loans in its campaign to add 100,000 farmers to the nation’s ranks each year.

Among them will probably be Sgt. Matt Holzmann, 33, a Marine at Camp Pendleton who spent seven months in Afghanistan. He did counterinsurgency work and tried to introduce aquaponics, a self-replenishing agricultural system, to rural villages.

His zeal for aquaponics led him to the farming class. “It’s a national security issue,” he said the other day outside a garage-turned-classroom filled with boxes of Dr. Earth Kelp Meal. “The more responsibly we use water and energy, the greater it is for our country.”

Mr. O’Gorman, a pacifist and a pioneer of the baby-lettuce business, started the coalition after his son joined the Coast Guard. The group recently received a grant from the Bob Woodruff Foundation, co-founded by the ABC News journalist who was wounded in Iraq, to provide farming fellowships for wounded young veterans.

“Beginning farming has become the cause du jour among young people with college degrees and trust funds,” Mr. O’Gorman said at the farm, where there were stacks of Mother Earth News magazines in the bathroom and a batch of fresh kale in the sink. “My gut sense is a lot of them won’t be farming five years from now. But these vets will.”

Mr. Archipley’s own journey into organic farming was somewhat serendipitous. He joined the Marines in response to the Sept. 11 terrorist attacks and married between his second and third tours in Iraq. The couple bought three acres of avocado orchards north of San Diego.

Mr. Archipley, whose looks bring to mind a surfer dude, found pleasure tending his grove after leaving the Marines and eventually secured a loan from the Agriculture Department to build a greenhouse. His farm now sells organic produce to Whole Foods Markets in San Diego and Los Angeles.

In 2007, the couple started training veterans informally, financing the effort themselves. The new course, administered through MiraCosta College, costs $4,500, with Camp Pendleton offering assistance for active-duty Marines.

Farming offers veterans a chance to decompress, Mr. Archipley said, but, more important, provides a sense of purpose. “It allows them to be physically active, be part of a unit,” he said. “It gives them a mission statement — a responsibility to the consumer eating their food.”

Even in this idyllic setting, it can be a challenging process. Mike Nelson Hanes, now 34, enlisted in the Marines at 18. In 1994, six days into his basic training in South Carolina, his drill instructor committed suicide with an M-16 rifle in front of 59 recruits.

“He blew his head off,” Mr. Hanes said. “That was right from the get-go, at age 18.”

In Baghdad, Mr. Hanes served as a .50-caliber machine gunner atop a Humvee. “I was the one they were trying to kill,” he said. He returned home with post-traumatic stress disorder, depression and a traumatic brain injury. He was homeless for over a year, managing nevertheless to get a degree in environmental social services.

“Being outside was my comfort zone — still is,” he said. Two years ago, he stumbled upon the Archipleys’ “Veterans for Sustainable Agriculture” booth at an Earth Day festival in Balboa Park in San Diego. Mr. Hanes still struggles but is gaining ground.

“One thing I’ve noticed about agriculture is that you become a creator rather than a destroyer,” he said amid ornamental eucalyptus shrubs.

John Maki, Camp Pendleton’s transition assistance program specialist, said the life experiences of young veterans equip them for demanding work. “For a comparable age, you won’t find people who have had as much responsibility,” he said. “They’ve been tasked with making life-and-death decisions.”

Weldon Sleight, dean of the University of Nebraska’s College of Technical Agriculture, which has six enrolled veterans, said discipline — a mainstay of the armed forces — was critically important in agriculture. “A lot of these rural vets have this wonderful knowledge base about agriculture,” he added. “But we’ve told them for years there’s no future in it.”

In Central Florida, Adam Burke, who left farming to join the military, came full circle, designing a wheelchair-accessible farm in which his signature “red, white and blueberries” grow in containers on elevated beds.

Mr. Burke, a Purple Heart recipient who suffered a traumatic brain injury in Iraq, recently opened a second farm. “Squeezing a ball in physical therapy gets monotonous,” he said. “And you don’t get the mist from the sprinklers or a cool breeze in a psychologist’s office.”

Matthew McCue, 29, formerly Sergeant McCue, runs Shooting Star CSA outside San Francisco with his partner, Lily Schneider, delivering boxes of organic produce directly to consumers.

He recalled how orchard farmers in Iraq pridefully shared their pomegranates, tomatoes and melons.

“You learn how to face death,” he said of his service in Iraq. But in farming, he learned, “There was life all around.”