Neurology:
Alzheimer's Plaques Reversed in Mice by Blocking Cholesterol Pathway

Metabolism:
Cellular Stress Appears to Link Obesity, Diabetes

Structural Biology:
Interdisciplinary Team Yields High-res Clathrin Model

Pathology:
Blood Flow Mechanics Affect Genetics in Vascular Cells

School History:
Book and Forum Recognize Achievement of African Americans at HMS

Medical Education:
Education Reform Aims for Longitudinal Clinical Experience

Muscle Loss Pathways Proliferate

Fine-particle Pollution Linked to Blood Pressure Boost

Human Cell Therapy Center Created at CBR Institute

Lieberman to Head Faculty Affairs

Five Faculty Members Become AAAS Fellows

Ground Broken for New Fenway Housing

Grant Funds HSPH Initiative for Preparedness Against Terrorism

Long-term Care: Averting a National Crisis

Front Page

Blood Flow Mechanics Affect Genetics in Vascular Cells

Each minute, our entire volume of blood completes a circuit through the cardiovascular system. It is the kind of traffic flow that would make city planners balk, but the body's blood vessels handle the onslaught so capably and ceaselessly, we tend to forget the feat they perform. Researchers are finding more and more that this continuous rush of blood is not simply a burden that blood vessels bear, but a central influence on their behavior--and on their failure in diseases like atherosclerosis.

From left, Guohao Dai, Michael Gimbrone, and Guillermo García-Cardeña have worked to recreate on a culture plate the effect of pulsing blood. (Photo by Steve Gilbert)

Pathologists have known for decades that plaques are selective in their location--they tend not to form in straight vascular chutes but in places where arteries branch and curve. The endothelial cells lining these spots are subjected to disturbed flows that are more erratic than the smooth laminar flow in straighter sections.

Early Impairment

This recent study is "the best example of a more sophisticated flow environment in vitro, which more closely approximates what happens in vivo."

Guohao Dai, a postdoctoral fellow in Gimbrone's lab, collaborated with the lab of Roger Kamm, professor of mechanical and biological engineering at MIT, to capture MRI data of the structure of carotid arteries in normal human subjects. The carotid artery is implicated in atherosclerotic plaques that cause strokes. As in other sites in the body, plaques tend to burgeon along the outer curve of forks in the artery, while regions away from these branches tend not to develop plaques. Using ultrasound, the team also gathered information about fluid flow in the arteries.

Dai then used specialized software to compile the imaging information about structure and fluid flow to calculate the exact forces occurring at each point along the endothelial surface. The software generated unique waveforms representing the relative shear stress felt at each point over time.

The team recreated these waveforms in cultured endothelial cells. Two waveforms were chosen as representative of the "athero-prone" section of the carotid sinus, where the flow is rougher, and an "athero-protective" area, where flow is regular. Gimbrone's group has spent the past two decades perfecting a device that can accurately recreate different kinds of shear stress on cells. A spinning cone rotates above the plated cells in a pulsing motion, driving fluid over them at a velocity programmed by a computer to mimic the waveforms recorded in humans.

The researchers then analyzed both sets of cultured cells using cDNA microarrays to see how the different forces affected gene expression. Of the 12,000 genes tested, a relatively small number were overexpressed in each set of cells. The "athero-protective" cells expressed several genes involved in preventing inflammation and clotting and in synthesizing the blood vessel dilator nitric oxide. The "athero-prone" cells expressed several pro-inflammatory genes, cell signaling molecules, and growth factors implicated in atherogenesis. Exposure to different forces also affected structural genes that regulate junctions between cells and organize the cytoskeleton. The results confirm the role of inflammation and cell proliferation involved in plaque formation and uncovered genes that have yet to be characterized in the disease.

Flow Engineering

Together the two approaches should shed light on the surprisingly complex responses of endothelial cells to their environment. The thin layer of endothelium that lines the body's blood vessels may seem as superficial as a coat of paint, but it adds up to 10 trillion cells that together display many of the activities of an organ. It not only regulates traffic into and out of blood vessels, but also actively controls the smooth muscle that surrounds it and the blood cells and platelets that rush through it.

"There are multiple risk factors that have been identified" for atherosclerosis, said Gimbrone. "But they all ultimately play out at the level of the endothelium." Whatever factors contribute to the disease, from high blood sugar to inflammation, only some of the endothelial cells will ultimately respond to them and contribute to the formation of atherosclerotic plaques. García-Cardeña and Gimbrone hope to use their system to screen for new drugs that protect vulnerable areas of the endothelium from the assaults of disease and to identify biomarkers that harbinger the development of atherosclerosis at its earliest stages.

--Courtney Humphries