Rules of Attraction
Authors: Leslie Mitch 
Published: August 2003

A clingy character's affinity for blood vessels might launch atherosclerosis, according to a new study that challenges the long-held view about the origin of this killer disease. The work suggests that platelets, the cells that help seal cuts, trigger fat buildup by adhering to artery linings. The discovery might lead to the development of new compounds that forestall the sometimes fatal attraction between these repair cells and blood vessel walls.
According to conventional wisdom, atherosclerosis begins when white blood cells burrow into the artery wall, settle down, and start absorbing blood-borne lipids. As corpulent cells pile up inside the artery lining and other kinds of cells crowd in, a gunky plaque congeals. Only if this lesion starts to crack or leak, the hypothesis goes, do platelets enter the scene, swarming in and triggering clot formation. Clots are dangerous because they can snap off and float through the circulatory system, eventually lodging in a narrow artery and causing a stroke or heart attack. "Platelets were thought to be responsible only for the complications of atherosclerosis," says Steffen Massberg, a vascular biologist at the Technical University in Munich, Germany. However, some test tube studies hinted that platelets were not Johnny-come-latelies; they might stick to pristine arterial surfaces and release chemicals that lure white blood cells, inciting plaque formation.
To test that possibility, Massberg and colleagues used mice engineered to develop atherosclerosis at a young age. After marking platelets and white blood cells with different colored tags, the team scanned the rodents' carotid arteries under the microscope. In young mice without arterial lesions, a constellation of platelets glowed on the vessel lining. White blood cells didn't show up in the artery walls until after plaque scars appeared. The staggered sequence implies that platelets, not white blood cells, are fomenting plaque buildup, says Massberg. Scientists already knew that platelets stick to the arterial wall in two steps, first hooking on loosely, then anchoring themselves. During the process, Maasberg and colleagues found, they crank up genes for molecules that summon white blood cells. To determine whether thwarting platelet attachment reduces plaque formation, the researchers dosed mice with antibodies that prevent platelets from hitching themselves to the vessel wall. Compared with a control antibody, the treatment shrank the area covered by fatty deposits by one-third.
"This is the first direct evidence that platelets are important for the early events in lesion formation," says Bruce Sachais, a pathologist at the University of Pennsylvania in Philadelphia. Some people might develop clogged arteries because they carry platelets that are gummier than normal or that spill extra amounts of the chemicals that attract white blood cells. Identifying and treating these individuals when they are in their 30s might ensure that their arteries are clear when they reach their 50s and 60s, he says. We already have a cabinetful of compounds that reduce the stickiness of platelets, says Massberg, but they block only the anchoring step. Interfering with other aspects of the process--including recruitment of white blood cells--might help plenty of patients avoid a sticky situation.
--Mitch Leslie; suggested by Amir Sadighi Akha

S. Massberg, K. Brand, S. Grüner, S. Page, E. Müller, I. Müller, W. Bergmeier, T. Richter, M. Lorenz, I. Konrad, B. Nieswandt, M. Gawaz, A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation.
J. Exp. Med.
196
, 887-896 (2002).
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