Mouse Model Suggests Mechanism for Development of Atherosclerosis

Researchers working with a mouse model have found that inactivation of the low-density lipoprotein receptor-related protein (LRP1) in vascular smooth muscle cells (SMCs) causes overexpression of the receptor for platelet-derived growth factor (PDGF) and abnormal activation of PDGF signaling, resulting in disruption of the elastic layer, SMC proliferation, aneurysm formation, and marked susceptibility to cholesterol-induced atherosclerosis.

"We used gene targeting to unravel a mechanism that controls and holds smooth muscle cell proliferation and migration in check,” said first author Dr. Philippe Boucher, postdoctoral researcher in molecular genetics at the University of Texas Southwestern Medical Center (Dallas, USA; www.utsouthwestern.edu). "This process is hyperactive in atherosclerosis.”

The findings were reported in the April 11, 2003, issue of Science. The investigators also reported that Gleevec, an inhibitor of PDGF signaling used successfully to treat chronic myeloid leukemia, was able to reduce atherosclerosis in the mouse model by about 50%.

There is no human clinical condition similar to that of the mouse model lacking LRP1. Nonetheless, this study emphasized the importance of PDGF signaling in the development of atherosclerosis.




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University of Texas Southwestern Medical Center