Abstract—Inflammation and vascular remodeling are hallmarks of atherosclerosis, hypertension, and restenosis after angioplasty. Here we investigated the role of the hepatocyte gp130-dependent systemic acute phase response on vascular remodeling after carotid artery ligation. Mice with a hepatocyte-specific gp130 knockout on an apolipoprotein E^-/- background (gp130^-) were compared with control mice (gp130^flox). Vascular remodeling was induced by permanent ligation of the left common carotid artery. This, in turn, activated the systemic acute phase reaction in gp130^flox mice, as measured by serum amyloid A plasma levels, which was completely abrogated in gp130^- mice (P<0.05). Morphometric analysis of the carotid artery revealed severe neointima formation and media thickening 28 days after ligation in gp130^flox mice, which was suppressed in gp130^- mice (P<0.01). Serial sections from gp130^- carotid segments showed significantly less smooth muscle cell (SMC) proliferation and monocyte recruitment (P<0.01). To evaluate the impact of the gp130-dependent systemic acute phase response on SMCs, hepatocytes from gp130^flox and gp130^- mice were stimulated with interleukin 6. Interleukin 6–induced secretion of serum amyloid A was completely abolished in gp130^- hepatocytes (P<0.01). Moreover, when stimulated with supernatants from gp130^- hepatocytes, SMCs showed significantly less migration and proliferation compared with supernatants from gp130^flox hepatocytes (P<0.01). Recombinant serum amyloid A induced SMC migration and proliferation (P<0.05) and serum amyloid A injection after carotid artery ligation restored vascular remodeling in gp130^- mice (P<0.01). These results imply a critical role for the gp130-dependent systemic acute phase response for vascular inflammation and SMC migration, as well as proliferation, and, subsequently, for vascular remodeling.