TGF-β signaling in atherosclerosis and restenosis

Abstract

Current theories suggest that atherosclerotic and restenotic lesions result from imbalances between systems that are proinflammatory/fibroproliferative versus the endogenous inhibitory systems that normally limit inflammation and vascular wound repair. Abnormalities in one of the major regulatory pathways, the transforming growth factor-β (TGF-β) system, has been characterized in both animal models and in human lesions and lesionderived cells. TGF-β signaling is capable of regulating many of the key aspects of atherosclerosis and restenosis: inflammation, chemotaxis, fibrosis, proliferation, and apoptosis. There are significant decreases in TGF-β activity in patients with atherosclerosis, and equally important changes in the way cells respond to TGF-β during atherogenesis. Evidence from multiple sources indicates that experimental modulation of TGF-β activity, or TGF-β responses, changes the course of atherosclerosis and intimal hyperplasia. Cells derived from human lesions produce adequate TGF-β levels, but are resistant to the antiproliferative and apoptotic effects of TGF-β. An evolving theory describes TGF-β as a major orchestrator of the vascular repair process, with observable defects in its production, activation, and cellular responses during the atherosclerotic and restenotic processes.