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(American Journal of Pathology. 2000;157:1247-1258.)
© 2000 American Society for Investigative Pathology

Regular Articles

p75NTR Mediates Neurotrophin-Induced Apoptosis of Vascular Smooth Muscle Cells

Shiyang Wang*, Paula Bray{dagger}, Timothy McCaffrey{dagger}, Keith March{ddagger}§, Barbara L. Hempstead{dagger} and Rosemary Kraemer*

From the Departments of Pathology*
and Medicine,{dagger}
Joan and Sanford I. Weill Medical College of Cornell University, New York, New York; and the Krannert Institute of Cardiology{ddagger}
and Richard L. Roudebush Veterans Administration Medical Center,§
Indiana University School of Medicine, Indianapolis, Indiana

The development of atherosclerotic lesions results from aberrant cell migration, proliferation, and extracellular matrix production. In advanced lesions, however, cellular apoptosis, leading to lesion remodeling, predominates. During lesion formation, the neurotrophins and the neurotrophin receptor tyrosine kinases, trks B and C, are induced and mediate smooth muscle cell migration. Here we demonstrate that a second neurotrophin receptor, p75NTR, is expressed by established human atherosclerotic lesions and late lesions that develop after balloon injury of the rat thoracic aorta. The p75NTR, a member of the tumor necrosis factor/FAS receptor family, can modulate trk receptor function as well as initiate cell death when expressed in cells of the nervous system that lack kinase-active trk receptors. p75NTR expression colocalizes to neointimal cells, which express smooth muscle cell {alpha}-actin and are expressed by cultured human endarterectomy-derived cells (HEDC). Areas of the plaque expressing p75NTR demonstrate increased TUNEL positivity, and HEDC undergo apoptosis in response to the neurotrophins. Finally, neurotrophins also induced apoptosis of a smooth muscle cell line genetically manipulated to express p75NTR, but lacking trk receptor expression. These studies identify the regulated expression of neurotrophins and p75NTR as an inducer of smooth muscle cell apoptosis in atherosclerotic lesions.




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