The Biology of TGF-beta and its role in Atherosclerosis

Our interest in the biology of TGF-beta has its origins in early studies of vascular smooth muscle cells (VSMCs).

VSMCs are the major cell type in the mammalian blood vessel wall and in the 1970s and early 1980s these cells were considered pivotal in atherogenesis. At that time, it was thought that atherosclerosis was caused by the inappropriate migration and proliferation of VSMCs from the blood vessel wall to form the atherosclerotic plaque, which occluded blood flow and resulted in angina. The ‘phenotypic transition’ hypothesis proposed that, under regulation from growth factors and other cytokines, VSMCs underwent a phenotypic transition from the contractile phenotype observed in healthy vessels to the synthetic and proliferative phenotype observed in atherosclerotic lesions. Working with Jim Metcalfe and Peter Weissberg in the Department of Biochemistry at Cambridge, Dr David Grainger looked for cytokines with the ability to promote the contractile phenotype of VSMCs and by implication inhibit atherogenesis. This search lead to transforming growth factor beta (TGF-beta); which was found to increase the expression of the proteins that compose the contractile apparatus, such as SM-alpha-actin and SM-myosin heavy chain, as well as inhibiting the proliferation and migration of the VSMCs and stimulating the production of extracellular matrix that stabilises the vessel wall (Biochem. J. 299:227).

Reasoning that atherogenesis is likely to be a balance between pro- and anti-atherogenic signals, and that loss of normal vessel wall architecture might as easily result from insufficient anti-atherogenic signals as from an excess of pro-atherogenic signals, the protective cytokine hypothesis was coined (Biol. Rev. 70:571).

Atherosclerosis is now viewed as a focal chronic inflammatory response, involving complex interactions between intimal endothelial cells, VSMCs and other cells of the immune system. However, as discussed in the following pages, the pleiotropic effects of TGF-beta mean that it remains the archetypal anti-atherogenic cytokine and therefore the protective cytokine hypothesis has gained increasing support over the last decade.

Active TGF-beta1 inhibits VSMC cell proliferation