PAI-1 may not drive nonthrombotic obstructive disease in vein grafts
MedWire News: A US study has challenged the concept that plasminogen activator inhibitor (PAI)-1 drives nonthrombotic obstructive disease in vein grafts.
The findings in mice suggest a multifaceted role for PAI-1 in regulating early remodeling of vein bypass grafts.
Decreased PAI-1 expression promoted intimal hyperplasia through pathways that did not require vitronectin and increased thrombin activity in vein grafts.
But although PAI-1 overexpression promoted the migration of smooth muscle cells in vitro, it did not increase intimal hyperplasia.
William Fay (University of Missouri School of Medicine, Columbia) and colleagues say their findings "suggest that PAI-1's antiproteolytic function, including its antithrombin activity, inhibits intimal hyperplasia."
The researchers note that approximately 40% of vein grafts occlude within 10 years of coronary bypass surgery, and that this is significantly more common than with arterial grafts.
They investigated the impact of alterations in PAI-1 expression on the development of vein graft intimal hyperplasia and its potential role as a thrombin inhibitor in the vein graft wall.
Studies in wild-type mice, those deficient in PAI-1, and those overexpressing PAI-1 revealed that PAI-1 regulates vein graft remodeling, with decreased expression leading to increased intimal hyperplasia.
The effects of PAI-1 were mediated not only by the plasma pool but also by a local vein-graft pool that is not discernable by measuring plasma PAI-1.
However, a primary increase in PAI-1 expressed locally in vein grafts or systemically did not increase vein graft intimal hyperplasia, the researchers report in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.
PAI-1 regulated the function of vein graft smooth muscle cells and regulated thrombin activity in vein grafts, they add.
The team believes these findings suggest that downregulation of PAI-1 could promote intimal hyperplasia by enhancing vitronectin-dependent smooth muscle cell migration and thrombin-induced smooth muscle cell proliferation.
"These findings are relevant to ongoing development of PAI-1 inhibitors to treat vascular disease - ie, pharmacological PAI-1 inhibition could potentially upregulate cell migration and vein graft wall thrombin activity," they say.
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By Anita Wilkinson