Do PAI-1 and vitronectin promote or inhibit neointima formation? The exact role of the fibrinolytic system in vascular remodeling remains uncertain.

Abstract

In this issue of Arteriosclerosis, Thrombosis and Vascular Biology , de Waard et al1 report enhanced neointima formation and luminal stenosis following carotid artery ligation in mice deficient for plasminogen activator inhibitor-1 (PAI-1) or vitronectin (VN) compared with their wild-type counterparts. Their findings appear to contradict those of a recently published study by Peng et al,2 thus adding fuel to the ongoing discussion and growing uncertainty about the exact role of PAI-1 and VN in the vascular remodeling process underlying atherosclerosis and restenosis. In this brief editorial, we review the evidence that suggests that PAI-1 and VN should influence this process, and then we attempt to reconcile the two publications. See page 1978 Interest in the involvement of the fibrinolytic system, and particularly PAI-1, in the development and complications of human atherosclerosis was sparked by several clinical studies which reported elevated plasma concentrations of the inhibitor in patients with acute coronary syndromes.3–5⇓⇓ In addition, histological observations consistently demonstrated that PAI-1 gene expression was upregulated in macrophages and smooth muscle cells (SMCs) present in human atherosclerotic lesions6–8⇓⇓ and in lesions that develop in animal models of atherosclerosis.9,10⇓ Finally, inflammatory proatherosclerotic mediators, including oxidized LDL, were shown to upregulate the expression of PAI-1 in endothelial cells and vascular SMCs in culture.11–13⇓⇓ Taken together, these observations implicate PAI-1 in the pathology of the vessel wall that develops in response to vascular insult. As the principal physiological inhibitor of plasminogen activation, PAI-1 would seem to play a key role in the regulation of vascular homeostasis at sites of arterial injury. This important function of PAI-1 is facilitated by VN, a 75-kDa glycoprotein that binds the inhibitor with high affinity, stabilizes the inhibitor in its active conformation, and mediates the binding of …