Arteries, the large blood vessels that carry oxygenated blood away from the heart and to the rest of the body, may play a far more important role in immune response than previously thought, suggests a new study by researchers at Emory University.
More than just circulation
Arteries have usually been defined strictly by their cardiovascular function. “Traditionally, what we know about arteries is that they function like tubes carrying the blood throughout the body,” says Cornelia Weyand, co-director of Emory’s Lowance Center for Human Immunology.
Most researchers have looked at the roles arteries play in common cardiovascular diseases such as high blood pressure, the contracting of blood vessel walls that results in increased pressure of blood against those walls; and atherosclerosis, the chronic inflammation in blood vessel walls often referred to as “hardening” of the arteries. Both conditions can result in heart attack or stroke.
But those investigating arterial disease, particularly vasculitides, which are characterized by inflammation of the blood vessel, have found that different arteries show remarkably different responses to the same cardiovascular risk factors. They call this variety of responses tropism.
“Physicians have long known that inflammatory vasculitides show very precise tropism in that they will affect certain blood vessels and not others,” Weyand says. “That tropism is so precise, in fact, that it is used diagnostically. Doctors look at where the disease is and then make their diagnosis based on that.”
Amir Lerman, a researcher at the Mayo Clinic in Rochester, Minn., has looked at this tropism as it applies to atherosclerosis.
“When you look at the distribution of plaques in this disease, humans have more of it in the coronary [heart] arteries than in the renal [kidney] ones, even though those arteries are exposed to the same risk factors,” Lerman says. “You have to ask yourself, why might someone have a certain disease in one vascular site and not another when that person is exposed to the same things? What is different?”
These are questions that have perplexed clinicians for some time. But Weyand’s research may have an answer: Arteries’ unique and location-specific roles in the immune system may be behind this tropism. Weyand and colleagues presented their current evidence in the Sept. 16 issue of Circulation. Weyand’s research is partially supported by the Dana Foundation.
“It is becoming clear that a disease like atherosclerosis is more than just the deposition of lipids in the vessel wall,” says Weyand. “Instead, it is the immune system launching an inflammatory response there.”
Looking for the sensors
Weyand and her colleagues hypothesized that arteries had some type of immune function. But before they could determine what that function might be, they first needed to establish that blood vessels were able to sense a potential threat.
One sensor is the Toll-like receptor (TLR), a receptor that binds with pathogens and diseased cells to alert the body to their potential danger. Weyand’s lab collected six different types of human blood vessels from different areas of the body and performed gene expression profiles on them to see if they could find evidence of TLRs.
The group did find abundant expression of TLRs, on a specialized population of cells in the arterial wall called dendritic cells. What’s more, the different vessels showed distinctive profiles of these receptors.
“We tested for nine different families of these TLRs,” says Weyand. “And each vessel showed a unique profile for the different types of receptors depending on where it sits in our body.” This makes sense, she says: Vessels near the gut would need to respond to different infectious agents than those located near the brain.
The discovery suggested that the arteries do have an immune sensing function and that it is specialized based on location. But the Emory group wanted to see it in action.
Hoping to stimulate the immune response, they grafted human blood vessels into a genetically modified mouse that is incapable of mounting an adaptive immune response. Then they transferred human T cells, a type of white blood cell that indicates infection, into the mice.
While the native mouse cells did not react, the dendritic cells in the grafted arteries sensed the T cells and initiated inflammation in response. The pattern of response was different based on what kind of infectious agent and what type of blood vessel was used.
“This tells us that the larger blood vessels have a much broader function than we previously thought,” Weyand says. “They possess a sensing system that allows them to detect danger signals and then communicate that danger to the immune system. And that communication differs depending on where they reside in the body.”
The bigger picture
Gary Hoffman, a researcher of rheumatic and immunologic disease at the Cleveland Clinic, hopes that this finding increases recognition that blood vessels are much more than just “tubular highways.”
“Blood vessels are highly specialized conduits that play unique and sub-specialized roles in the body from the third week of embryonic development up through adulthood,” he says. “But Weyand’s paper shows us that there is a dialogue between the blood vessel and the tissues it supplies, that there really is cross-talk between the blood vessel and the immune system.”
Weyand says researchers have only scratched the surface of what there is to know of arteries’ immunologic function.
“Our hypothesis is that dendritic cells’ natural role is to keep inflammation out of our blood vessels,” she says. “When we do develop inflammation, it is a failure of that protective mechanism.” The Emory team plans to look more closely at the mechanism and where it may go awry as well as how blood vessels may have developed this interesting cardiovascular and immune job-sharing role.
Hoffman also sees clinical implications.
“To date, we’ve had a very naïve understanding of the differences of blood vessels and how they relate to disease,” he says. “But these insights will open up a whole new area of investigation that may bring us a lot closer to understanding the dynamics of vasculitis and how to treat it.”