Plasminogen activator inhibitor-1 regulates the vascular expression of vitronectin.

Essentials Vitronectin (VN) is produced by smooth muscle cells (SMCs) and promotes neointima formation. We studied the regulation of vascular VN expression by plasminogen activator inhibitor-1 (PAI-1). PAI-1 stimulates VN gene expression in SMCs by binding LDL receptor-related protein 1. Stimulation of VN gene expression may be a mechanism by which PAI-1 controls vascular remodeling. Background Increased expression of vitronectin (VN) by smooth muscle cells (SMCs) promotes neointima formation after vascular injury, and may contribute to chronic vascular diseases, such as atherosclerosis. However, the molecular regulation of vascular VN expression is poorly defined. Given the overlapping expression profiles and functions of VN and plasminogen activator inhibitor (PAI)-1, we hypothesized that PAI-1 regulates vascular VN expression. Objectives To determine whether PAI-1 regulates VN expression in SMCs and in vivo. Methods The effects of genetic alterations in PAI-1 expression, pharmacologic PAI-1 inhibition and recombinant PAI-1 on SMC VN expression were studied, and vascular VN expression in wild-type (WT) and PAI-1-deficient mice was assessed. Results VN expression was significantly lower in PAI-1-deficient SMCs and significantly increased in PAI-1-overexpressing SMCs. PAI-1 small interfering RNA and pharmacologic PAI-1 inhibition significantly decreased SMC VN expression. Recombinant PAI-1 stimulated VN expression by binding LDL receptor-related protein-1 (LRP1), but another LRP1 ligand, α