Cardiotrophin-1 (CT-1) is a cytokine belonging to the interleukin-6 superfamily that exhibits trophic and survival properties in a number of cell types. CT-1 expression has recently been identified within the media of atherosclerotic arteries, but its role in the vessel remains unknown. The aim of this study is to characterize CT-1 actions and regulation in vascular smooth muscle cells (VSMC). Primary rat aorta VSMC were stimulated with CT-1 (10⁻¹¹–10⁻⁹M) for up to 48 hours, without and with antibodies against CT-1 receptors. Moreover, the effects of aldosterone (10⁻⁸–10⁻⁶M) and angiotensin II (10⁻⁹–10⁻⁷M) on CT-1 expression were evaluated. Cell proliferation was determined by MTT assay. The expression of CT-1, collagen type I, and fibronectin was quantified by Western blot. Matrix metalloproteinases (MMPs) activities were assessed by gelatin and casein zymographies. A 48-hour treatment with CT-1 induced VSMC proliferation in a dose-dependent manner (p<0.01). A 24-hour incubation with CT-1 led to an increased expression of collagen type I (p<0.01) and fibronectin (p<0.05), with a parallel and dose-dependent increase in active MMP-2 (p<0.01), MMP-3 (p<0.05) and MMP-9 (p<0.01), all of these effects being reversed in the presence of antibodies against CT-1 receptors. Whereas VSMC spontaneously expressed CT-1, both aldosterone and angiotensin II enhanced (p<0.01) CT-1 expression in these cells in a dose- and time-dependent manner. CT-1 induces proliferation and a secretory phenotype in VSMC. Upregulation of CT-1 expression by angiotensin II and aldosterone in VSMC suggests a mediator role for this cytokine in alterations of these cells caused by the RAAS in vascular diseases.