Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis.

The role of the anti-inflammatory cytokine transforming growth factor beta (TGF-beta) in atherosclerosis has been the subject of considerable debate for a decade. In the early 1990s, we postulated that TGF-beta played an important role in maintaining normal vessel wall structure and that loss of this protective effect contributed to the development of atherosclerosis. We termed this the protective cytokine hypothesis. This proposal was slow to gain broad acceptance, however, because at that time there were little data available on the role of TGF-beta during the development of atherosclerosis but much information about its role during trauma-induced neointima formation. Because TGF-beta apparently aggravates neointima formation, both by inhibiting endothelial regeneration and by promoting fibrosis, it was difficult to accept that its presence might ameliorate the superficially similar atherogenesis process. But several recent studies revealed beyond doubt the fact that TGF-beta protects against lipid lesion formation, at least in mouse models of atherosclerosis. Therefore, two important questions remain. First, is the role of TGF-beta in vascular biology similar in humans and in mice? Secondly, how important, compared with defects in thrombosis or lipoprotein metabolism, is the protective role of TGF-beta during atherogenesis?