4 years ago

Plasminogen Activator Inhibitor-1 Regulates the Vascular Expression of Vitronectin

Y. Ji, M. Luo, W. P. Fay, Y. Luo, J. Wu, R. Li
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-1 (PAI-1), we hypothesized that PAI-1 regulates vascular VN expression Objectives Determine whether PAI-1 regulates VN expression in SMCs and in vivo. Methods 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-over-expressing SMCs. PAI-1 siRNA and pharmacological 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, α2-macroglobulin, did not. Compared to WT controls, carotid artery VN expression was significantly lower in PAI-1-deficient mice and significantly higher in PAI-1-transgenic mice. In a vein graft (VG) model of intimal hyperplasia, VN expression was significantly attenuated in PAI-1-deficient VGs compared to WT controls. Plasma VN concentration was significantly decreased in PAI-1-deficient mice vs. WT controls at 4 weeks, but not at 5 days or 8 weeks, after surgery Conclusions PAI-1 stimulates SMC VN expression by binding LRP1 and controls vascular VN expression in vivo. Autocrine regulation of vascular VN expression by PAI-1 may play important roles in vascular homeostasis and pathological vascular remodeling. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/jth.13869

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