Objective—Impairment of transforming growth factor (TGF)-1 signaling accelerates atherosclerosis in experimental mice. However, it is uncertain whether increased TGF-1 expression would retard atherosclerosis. The role of TGF-1 in aneurysm formation is also controversial. We tested whether overexpression of active TGF-1 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-1 in their hearts. Compared to littermate controls, these mice had elevated cardiac and plasma TGF-1, less aortic root atherosclerosis (P0.002), fewer lesions in the thoracic and abdominal aortae (P0.01), less aortic root dilation (P<0.001), and fewer pseudoaneurysms (P=0.02). Mechanistic studies revealed no effect of TGF-1 overexpression on plasma lipids or cytokines, or on peripheral lymphoid organ cells. However, aortae of TGF-1–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-1 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.