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Overexpression of endogenous SO<jats:sub>2<\/jats:sub> synthase aspartate aminotransferase (AAT) 1 or 2 increased SO<jats:sub>2<\/jats:sub> levels and inhibited collagen I and III expressions induced by transforming growth factor (TGF)-\u03b21 in VSMCs. In contrast, AAT1 or AAT2 knockdown induced a severe collagen deposition in TGF-\u03b21-treated VSMCs. Furthermore, AAT1 or AAT2 overexpression suppressed procollagen I and III mRNA, upregulated matrix metalloproteinase (MMP)-13 expression, downregulated tissue inhibitors of MMP-1 level and vice versa. Mechanistically, AAT1 or AAT2 overexpression inhibited phosphorylation of type I TGF-\u03b2 receptor (T\u03b2RI) and Smad2\/3 in TGF-\u03b21-stimulated VSMCs. Whereas SB431542, an inhibitor of TGF-\u03b21\/Smad signaling pathway, attenuated excessive collagen deposition induced by AAT knockdown. Most importantly, ectopically expressing AAT or exogenous addition of 100\u2009\u03bcM SO<jats:sub>2<\/jats:sub> blocked AAT deficiency-aggravated collagen accumulation in TGF-\u03b21-stimulatd VSMCs, while no inhibition was observed at 100\u2009\u03bcM ethyl pyruvate. 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