TGF-β1 Limits Plaque Growth, Stabilizes Plaque Structure, and Prevents Aortic Dilation in Apolipoprotein E-Null Mice

Objective— Impairment of transforming growth factor (TGF)-β1 signaling accelerates atherosclerosis in experimental mice. However, it is uncertain whether increased TGF-β1 expression would retard atherosclerosis. The role of TGF-β1 in aneurysm formation is also controversial. We tested whether overexpression of active TGF-β1 in hyperlipidemic mice affects atherogenesis and aortic dilation. Methods and Results— We generated apolipoprotein E-null mice with transgenes that allow regulated overexpression of active TGF-β1 in their hearts. Compared to littermate controls, these mice had elevated cardiac and plasma TGF-β1, less aortic root atherosclerosis ( P ≤0.002), fewer lesions in the thoracic and abdominal aortae ( P ≤0.01), less aortic root dilation ( P <0.001), and fewer pseudoaneurysms ( P =0.02). Mechanistic studies revealed no effect of TGF-β1 overexpression on plasma lipids or cytokines, or on peripheral lymphoid organ cells. However, aortae of TGF-β1-overexpressing mice had fewer T-lymphocytes, more collagen, less lipid, lower expression of inflammatory cytokines and matrix metalloproteinase-13, and higher expression of tissue inhibitor of metalloproteinase-2. Conclusions— When overexpressed in the heart and plasma, TGF-β1 is an antiatherogenic, vasculoprotective cytokine that limits atherosclerosis and prevents aortic dilation. These actions are associated with significant changes in cellularity, collagen and lipid accumulation, and gene expression in the artery wall.