Plasminogen activator‐1 overexpression decreases experimental postthrombotic vein wall fibrosis by a non‐vitronectin‐dependent mechanism

Abstract

SUMMARY Background Factors associated with post-thrombotic syndrome are known clinically, but the underlying cellular processes at the vein wall are not well-delineated. Prior work suggests that vein wall damage does not correlate with thrombus resolution, but rather with plasminogen activator-1 (PAI-1) and matrix metalloproteinase (MMP) activity. Objective We hypothesized that PAI-1 would confer post venous thrombosis (VT) vein wall protection via a Vitronectin (Vn) dependent mechanism. Methods A stasis model of VT was used with harvest over 2 weeks, in wild type (WT), Vn−/−, and PAI-1 overexpressing mice (PAI-1 Tg). Results PAI-1 Tg mice had larger VT at 6 and 14 days, compared to controls, but Vn−/−mice had no alteration of VT resolution. Gene deletion of Vn resulted in increased, rather than expected decrease in circulating PAI-1 activity. While both Vn−/− and PAI-1 Tg had attenuated intimal fibrosis, PAI-1 Tg had significantly less vein wall collagen and a compensatory increase in collagen III gene expression. Both Vn−/− and PAI-1 Tg vein wall had less monocyte chemotactic factor-1, and fewer macrophages (F4/80), with significantly less MMP-2 activity and decreased TIMP-1 antigen. Ex vivo assessment of TGFβ mediated fibrotic response showed that PAI-1 Tg vein walls had increased profibrotic gene expression (collagen I, III, MMP-2 and α-SMA) as compared with controls, opposite of the in vivo response. Conclusions The absence of Vn increases circulating PAI-1, which positively modulates vein wall fibrosis in a dose-dependent manner. Translationally, PAI-1 elevation may decrease vein wall damage after DVT, perhaps by decreasing macrophage-mediated activities.

TGF-β1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology

“…The reduction of type I and III collagen secretion by VSMC is induced through TGF-β1/Smad3 signaling pathway inhibition [ 93 ]. Expression levels of PAI-1, the major physiological regulator of the plasmin-based pericellular proteolytic cascade, are also linked to TGFβ1-induced neointimal expansion [ 89 ], although the actual role of PAI-1 in the development of a VSMC-rich neointima is likely to be complex [ 94 , 95 ].…”

Serpins in Venous Thrombosis and Venous Thrombus Resolution

“…Additionally the endothelial cell marker, CD31 and vein wall smooth muscle cell (VSMC) gene expression were enhanced in PAI-1 deficient models, suggesting a role for PAI-1 in endothelial integrity and vein wall remodeling (24). Consistent with this, transgenic mice overexpressing PAI-1 showed impaired thrombus resolution, although paradoxically, had significantly less collagen deposition in the vein wall, resulting in decreased vein wall fibrosis (25). …”

Libby amphibole‐induced mesothelial cell autoantibodies bind to surface plasminogen and alter collagen matrix remodeling

“…; Obi et al. ). Deficiencies in plasmin or plasminogen activator have led to increased fibrosis (de Giorgio‐Miller et al.…”

“…A review of the literature revealed a precedent with regard to the role of plasminogen in fibrosis. Activation of the plasminogen/plasmin system has been shown to slow progression of fibrosis in experimentally induced asbestos disease for murine models (Hattori et al 2004;Obi et al 2014). Deficiencies in plasmin or plasminogen activator have led to increased fibrosis (de Giorgio-Miller et al 2005).…”