Activation of the tgfΒ/activin signaling pathway in intimal hyperplasia and atherosclerosis

Abstract

Intimal hyperplasia and atherosclerosis are the Achilles' heels of vascular interventions. Many cytokines and growth factors have been shown to mediate these pathological processes. There are conflicting data concerning the expression of transforming growth factor-β1 (TGFβ1) antigen in human intimal hyperplasia and atherosclerotic lesions and conflicting views about whether TGFβ1 is pro- or anti-atherogenic. The presence of TGFβ1 is not sufficient to infer activation of its signaling pathway because TGFβ1 may be present in inactive complexes. A sensitive immuno-fluorescence assay (cyanine-3 tyramide signal amplification system) was used on human coronary artery and aorta sections with early or advanced stage lesions to detect TGFβ1, activin, Smad2-P, a marker of the activated TGFβ1/activin pathway and components of latent TGFβ complexes. All antigens were readily detected in the media and neointima of early stage lesions. The levels were either reduced or undetectable in the media of advanced lesions but were increased in the neointima in areas of high cell density. In marked contrast to activin, TGFβ1 and LAP1 expression levels were closely correlated with Smad2-P throughout the artery wall. Discrepancies in previous data for TGFβ1 expression are probably due to assay sensitivity. TGFβ1, but not activin, expression is consistently correlated with Smad pathway activation in the artery wall. The pattern of Smad2 activation supports a model in which TGFβ/activin signaling is anti-atherogenic in the media of normal artery walls but is equally compatible with an anti-atherogenic or pro-atherogenic response to TGFβ/activin in the neointima of lesions.