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BETTER UNDERSTANDING
UVA researchers Brett Blackman, Ph.D., Assistant Professor of Biomedical Engineering, and Brian Wamhoff, Ph.D., Assistant Professor of Medicine, have teamed up to create a novel human cell-based model to study heart disease outside the human body. The model is used to study atherosclerosis – a disease affecting blood vessels that causes hardening and narrowing of the arteries and can lead to heart attack or stroke. An inflammatory disease, atherosclerosis tends to occur at locations in the arteries where blood flow is compromised and the altered shear stress – or the stress of the blood flow acting against the walls of the blood vessels – causes endothelial cells (cells lining the interior of blood vessels) and smooth muscle cells (cells found in the wall of blood vessels) to undergo detrimental changes. The researchers’ device, HemoShear 2.0, exposes human endothelial and smooth muscle cells (or any other type of cells the researcher wishes to pair with endothelial cells) to pulsatile features of blood flow in the human body (i.e. hemodynamic blood flow). The device also measures and records data from this exposure. “By using the data on the velocity of blood in different arteries as obtained by MRI,” says Blackman, “we are able to simulate actual flow patterns in atheroprone areas [arteries that are more susceptible to atherosclerosis] and atheroprotective areas [arteries that are less susceptible to atherosclerosis] and observe how the cells respond to these flow patterns.” This type of research, Wamhoff adds, hasn’t previously been performed. “Research has been conducted where human cells are isolated to observe behavior patterns, but there are no available models that allow researchers to accurately study the intricate communication between endothelial cells and smooth muscle cells in a setting that mimics hemodynamic blood forces in the body.” This communication is important because endothelial cells recognize different blood-flow patterns and respond by expressing or repressing genes. Those gene expressions influence their interactions with the smooth muscle cells –interactions that the researchers found may lead to early-inflammation-associated atherosclerosis in arteries with altered shear stress. Using HemoShear, the researchers mimicked atheroprone and atheroprotective circulatory environments. Endothelial cells were plated on the top surface of a synthetic version of a blood vessel wall, and smooth muscle cells were plated on the bottom surface. Then, atheroprone or atheroprotective arterial-flow patterns modeled from human circulation were applied to the endothelial cells through rotation of a motor-driven cone system. The findings: hemodynamic flow can influence the behavior of both endothelial and smooth muscle cells. In the presence of atheroprotective flow, the endothelial cells aligned with the direction of the blood flow and the smooth muscle cells aligned perpendicularly to the flow, behaving as they would in a healthy blood vessel. In stark contrast, atheroprone flow caused the endothelial cells to move away from their parallel structure and smooth muscle cells to move away from their perpendicular structure. These changes in structure mimic the early phases of a diseased artery. Atheroprone flow induced inflammation in both cells reminiscent of the early signs of atherosclerosis. This was confirmed by evaluating gene and protein expression profiles in both cell types. A provisional patent application has been filed for HemoShear 2.0. The research that HemoShear made possible was spearheaded by a biomedical engineering graduate student, Nicole Hastings, and has been accepted for publication in the American Journal of Physiology – Cell Physiology. “The results of this study validate the use of this novel co-culture system as a relevant biometric vascular model for studying early atherosclerotic events,” says Tom Skalak, Ph.D., Chair of UVA’s Department of Biomedical Engineering. “The cells’ responses to these carefully controlled shear stresses can now be used to develop therapeutic interventions for detection and treatment of vascular diseases. It has the potential to be revolutionary.” HemoShear is unique because it can help test the effectiveness of drug compounds and aid in early-stage toxicity studies. Instead of testing drug compounds on isolated cells, which can produce false negatives, drug companies can now test compounds in a more realistic environment, resulting in more meaningful data and potentially speeding creation of useful drug treatments. Collaboration was key to the successful development of HemoShear and the research it makes possible. “The exciting research done by Drs. Blackman and Wamhoff is a testament to the collaborative spirit found at the University of Virginia,” says Sharon Hostler, M.D., Interim Vice President and Dean at the University of Virginia School of Medicine. “Their work could hold the key in the area of translational research, shortening the time it takes for a new therapy or procedure to go from the laboratory bench to helping patients.” The researchers have formed a collaborative entity – the Laboratory of Atherogenesis – to begin using the HemoShear system to make these translatable discoveries in atherosclerosis. “There is a real need for biometric models like the one Professors Blackman and Wamhoff have developed,” says UVA School of Engineering Dean James H. Aylor. “When collaborations among the intersecting fields of engineering, medicine and biotechnology occur, the potential innovations are limitless.” For more information, visit the Laboratory of Atherogenesis at http://faculty.virginia.edu/labofatherogenesis
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Every second, the human body performs thousands of functions and enables millions of processes. In the circulatory system alone there are a variety of cells and organs interacting with – and affecting – each other on a constant basis. Although these interactions could hold the key to understanding how diseases begin, improving diagnoses and creating effective treatments, they have proven difficult to study. Realistically emulating the body’s complex processes in the laboratory has been impossible – until now.