10:23 AM

Research to examine how blood flow influences plaque buildup

Engineering professor receives $1.8 million federal grant to investigate

Atherosclerosis—the narrowing of arteries due to plaque buildup—is the underlying reason for the majority of strokes and heart attacks. When atherosclerosis occurs in the arteries that carry blood to the heart muscle, it is called coronary artery disease, the No. 1 killer of Americans.

Biomedical Engineering Professor Rita Alevriadou has spent most of her career, which spans two decades, on cardiovascular disease. Her current research on the effects of blood flow on our artery walls recently earned attention and funding from the National Institutes of Health (NIH).

While much about atherosclerosis is unknown, most medical researchers agree that it begins with damage to the endothelium, the arteries’ smooth interior surface. Damage to the layer of endothelial cells leads to the formation of plaque, made up of fat, cholesterol, calcium, and other substances and cells in the blood. High blood pressure, abnormal cholesterol levels, cigarette smoking and diabetes are often cited as the most common causes of the damage.

But in an effort to better understand the disease’s initiation and progression, Alevriadou and her research team want to go with the flow. More precisely, how the flow of blood in our arteries, also known as hemodynamics, contributes to the endothelial damage.

Decades ago, according to Alevriadou, bioengineering pioneers discovered that plaques develop on the inner walls of curvatures and the outer wall of artery bifurcations—or forks. Since then, Alevriadou and other researchers around the world have focused on how blood flow in these arterial locations affects the function of endothelial cells.

“My research is focused on the very initial event, when the endothelial cells start to lose their normal function and respond to damage,” she said. “If we understand these initial effects and keep the endothelial cells healthy, we can delay the progression of cardiovascular disease.”

Alevriadou’s team is particularly interested in the inner workings of endothelial cells—called intracellular signaling—when they are exposed to different types of blood flow, specifically pulsatile and oscillatory. Pulsatile flow is in rhythm with the heartbeat, occurs in the straight parts of arteries and is characterized by high mean flow rates. Oscillatory flow occurs in arterial curvatures and bifurcations and is characterized by low—close to zero—mean flow rates.

“We know that the areas in arteries that develop atherosclerosis are the ones that are exposed to a certain flow profile, specifically oscillatory flow, or oscillatory shear stress,” Alevriadou said.

In the lab, the research team cultures human or bovine endothelial cells on slides, which are then inserted into perfusion chambers. A pump propels cultured media through the chambers, mimicking blood flow over the cells. Under the microscope, they observe in real-time how intracellular components behave, especially the mitochondria, the cell’s power plant.

$1.8 million, four-year NIH grant will fund their investigation of calcium transport in and out of the mitochondria as the potential origin of endothelial dysfunction and damage that can initiate and propagate atherosclerosis.

Alevriadou’s collaborator is University of Texas Health San Antonio Endowed Professor of Medicine Dr. Madesh Muniswamy. A mitochondrial calcium expert, he provided endothelial cell lines and transgenic mouse models enabling focus on the calcium channel called mitochondrial calcium uni­porter (MCU), which allows calcium to go into the mitochondria. The regular function of cells depends heavily on calcium and how it responds to different stimuli acting upon the cells. In this case, the stimulus acting upon the endothelial cells is blood flow or shear stress.

“In the literature, the majority of research is on cell responses to chemical stimuli,” Alevriadou said. “That’s where bioengineers separate ourselves from biologists and biochemists. We study cell responses to mechanical or electrical stimuli.”

The team has hypothesized that under oscillatory shear stress, the MCU may not operate as intended, leading to cell dysfunction, which may contribute to atherosclerotic disease.

“When the mitochondria are dysfunctional, they create a lot of free radicals that damage cellular components leading to cell dysfunction or apoptosis,” she added.

By mimicking artery hemodynamics, Alevriadou hopes to discover mechanochemical phenomena related to calcium in the mitochondria that may lead to better drugs or treatments for cardiovascular diseases.

“I believe the NIH wants to see innovative ideas, especially those that come from collaborative efforts between engineering and medicine,” she said. “Our initial goal is to identify a critical target, then discover and test small molecules that might modify the activity of the MCU.”

Alevriadou said contributions to this work have come from her former and current team members, including Randy Giedt (currently at Novartis Institutes for BioMedical Research), Christopher Scheitlin (currently at Battelle Memorial Institute), biomedical engineering graduate student Akshar Patel and undergraduate student Thomas Esber.