Transforming growth factor-β and atherosclerosis: interwoven atherogenic and atheroprotective aspects

Age-related progression of cardiovascular disease is by far the largest health problem in the US and involves vascular damage, progressive vascular fibrosis and the accumulation of lipid-rich atherosclerotic lesions. Advanced lesions can restrict flow to key organs and can trigger occlusive thrombosis resulting in a stroke or myocardial infarction. Transforming growth factor-beta (TGF-beta) is a major orchestrator of the fibroproliferative response to tissue damage. In the early stages of repair, TGF-beta is released from platelets and activated from matrix reservoirs; it then stimulates the chemotaxis of repair cells, modulates immunity and inflammation and induces matrix production. At later stages, it negatively regulates fibrosis through its strong antiproliferative and apoptotic effects on fibrotic cells. In advanced lesions, TGF-beta might be important in arterial calcification, commonly referred to as "hardening of the arteries". Because TGF-beta can signal through multiple pathways, namely the SMADs, a MAPK pathway and the Rho/ROCK pathways, selective defects in TGF-beta signaling can disrupt otherwise coordinated pathways of tissue regeneration. TGF-beta is known to control cell proliferation, cell migration, matrix synthesis, wound contraction, calcification and the immune response, all being major components of the atherosclerotic process. However, many of the effects of TGF-beta are essential to normal tissue repair and thus, TGF-beta is often thought to be "atheroprotective". The present review attempts to parse systematically the known effects of TGF-beta on both the major risk factors for atherosclerosis and to isolate the role of TGF-beta in the many component pathways involved in atherogenesis.