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• W2016031258 abstract "‘Is there any point to which you would wish to draw my attention?’ ‘To the curious incident of the dog in the night-time’. ‘The dog did nothing in the night-time’. ‘This was the curious incident’, remarked Sherlock Holmes. Silver Blaze by A. Conan Doyle Several lines of evidence support the notion that plasminogen activator inhibitor (PAI)-1 is a physiologically relevant regulator of vascular homeostasis. In particular, the results of recent studies leave little doubt that the inhibitor is capable of stabilizing fresh arterial thrombi forming after endothelial injury in vivo[1, 2]. It is thus possible not only that PAI-1 helps prevent excessive bleeding at sites of vascular trauma, but that it may also promote arterial thrombosis after rupture of atherosclerotic plaques [3]. In addition, and importantly, the role of PAI-1 and the fibrinolytic system may extend far beyond the modulation of acute vascular occlusion and recanalization. In fact, thrombosis and thrombus organization appear to be key events in vascular wall inflammation and the chronic wound healing response to endothelial injury [4, 5]. It would therefore seem reasonable to assume that the prothrombotic (antifibrinolytic) factor PAI-1 contributes to atherosclerosis, atherothrombosis, and neointimal growth, and that it could represent a potential target for future strategies to prevent myocardial infarction and/or restenosis. However, recent studies which used elegant animal models of atherosclerosis and vascular injury revealed that, if there is a role for PAI-1 in vascular remodeling, it must be much more complex than originally anticipated [6]. The report by Lijnen and coworkers in this issue of the Journal of Thrombosis and Haemostasis[7] adds further fuel to the ongoing debate by showing that overexpression of PAI-1 in mice, which resulted in significantly elevated levels of the inhibitor in the circulation, had no effect on neointima formation after arterial injury. Do these findings presage the end for PAI-1 in chronic vasculopathy, or do they just add another piece to the puzzle of what has been termed ‘the PAI-1 paradox’ in vascular biology [8, 9]? There is compelling epidemiological evidence that high plasma levels of PAI-1 are associated with coronary atherosclerosis and, particularly, with the occurrence of acute coronary syndromes in humans [10, 11]. Recently, acute release of PAI-1 was found to be a predictor of mortality in the acute phase of myocardial infarction with ST-segment elevation [12]. These clinical data are supported by a number of histological observations which reported increased mRNA and protein expression of the inhibitor in human atherosclerotic plaques [13, 14]. Moreover, significant upregulation of PAI-1 in the vessel wall was demonstrated in animal models of atherosclerosis [15] and neointima formation after arterial injury [1, 16], and oxidized LDL stimulated PAI-1 expression in cultured endothelial and vascular smooth muscle cells [17, 18]. Notwithstanding the consistency of these findings, the increased local (vascular) expression and plasma concentrations of PAI-1 in atherosclerosis are not sufficient to prove a causative role for the inhibitor in this condition. For example, PAI-1 is known to be upregulated by inflammatory cytokines, and its presence could simply represent a ‘by-product’ of the acute-phase response which accompanies atherosclerosis and restenosis. In addition, the elevation of circulating PAI-1 levels in acute coronary syndromes might be secondary to the activation of the renin–angiotensin–aldosterone system. In this regard, it has been shown that angiotensin II induces the expression of PAI-1 in cultured endothelial cells [19], and that treatment with angiotensin-converting enzyme (ACE) inhibitors reduces PAI-1 antigen and activity levels in humans [20]. Another important mechanism relates to the synthesis of PAI-1 (and other prothrombotic factors) in the adipose tissue and its upregulation in the presence of obesity and the metabolic syndrome [21, 22]. In fact, some clinical observations suggest that the prognostic value of increased PAI-1 levels with regard to cardiovascular risk disappears after adjustment for metabolic parameters related to insulin resistance [10, 23]. Finally, studies in apolipoprotein E (apoE)-knockout mice revealed that fibrin(ogen), which is cleaved as a result of plasminogen activation and stabilized by PAI-1, is not essential for the formation of advanced atherosclerotic lesions [24]. Does this mean that PAI-1 is no more than an ‘innocent bystander’ in vasculopathy? Probably not, since a growing number of observations suggest the opposite. For example, although the assessment of atherosclerotic lesions in apoE-knockout mice yielded conflicting results with regard to the pathophysiological relevance of the inhibitor [25-27], transgenic mice expressing a stable form of human PAI-1 in the endothelium were recently shown to develop coronary arterial thrombosis and subendocardial infarction [28]. Of note, in this study, spontaneous arterial thrombosis occurred in the PAI-1-overexpressing mice despite the absence of severe metabolic abnormalities such as excessive hypercholesterolemia. Further important (but also confusing) insights into the involvement of PAI-1 in vascular remodeling were gained by studies which focused on the wound healing response to experimental arterial injury. In a recent editorial [6], we reviewed and attempted to reconcile the results of these studies. In particular, we argued that the relationship between the severity of neointimal growth and the levels of PAI-1 may depend, at least in part, on the presence of thrombus/fibrin within the vessel after injury. For example, the absence of PAI-1 results in reduced neointima formation and luminal stenosis after arterial injury induced by ferric chloride [15], a copper/silicone cuff [29], or, in some cases, carotid artery ligation [30]. In these models, which are characterized by a marked thrombotic reaction and fibrin deposition in the arterial wall [1, 29, 31], the antifibrinolytic factor PAI-1 stabilizes the arterial thrombi and thus allows them to organize and participate in neointimal growth during the remodeling process [4, 5, 31]. On the other hand, in studies which used different models and/or observed a less prominent thrombotic response to injury, PAI-1 appeared to inhibit rather than enhance neointima formation [32, 33]. These results remind us that the effects of the plasminogen–plasmin system on the interactions between cells and the surrounding extracellular matrix are not confined to fibrin degradation. In fact, by inhibiting urokinase-type plasminogen activator (uPA)-mediated pericellular proteolysis, PAI-1 could stabilize the extracellular matrix and inhibit smooth muscle cell (SMC) migration within the vessel wall. Alternatively, or in addition to that mechanism, PAI-1 may bind to the somatomedin B domain of vitronectin and thus prevent both uPA receptor-mediated and integrin-mediated cell attachment to this extracellular matrix protein [6]. However, to make the pleiotropic effects of PAI-1 even more complicated, a recent study showed that PAI-1 can paradoxically enhance, rather than impair, SMC migration under certain circumstances [34], possibly depending on the cellular phenotype, the chemotactic stimulus, and the composition of the extracellular matrix [8]. Apart from the theoretical considerations discussed above, a number of methodological issues have to be taken into account when trying to reconcile the findings of experimental studies and resolve the PAI-1 paradox. In particular, arterial injury may elicit a variable thrombotic response in vivo, and the amount of thrombus, which is stabilized by PAI-1 and forms the provisional matrix for neointimal growth, may be very difficult to standardize. Because of this, even studies which use the same type of injury can reach different, sometimes opposite conclusions [30, 33]. This important limitation may also apply to the electrical injury model used by Lijnen et al. in the present study [7], and it could partly explain why these authors obtained results which were different from those reported by Carmeliet et al. a few years ago [32]. Although Lijnen et al. state that their model caused persistent thrombus formation, no histological findings of acute arterial injury and thrombosis are provided. Moreover, it is not entirely clear how drastically this model was modified compared with the earlier studies, in which thrombosis, although present, did not appear to be particularly prominent [35]. It can be assumed that, in the present study, in which the transgenic mice exhibited a significant but not massive elevation of PAI-1 levels, the direct inhibitory effects of PAI-1 on SMC migration may have been counterbalanced by the presence of neointima-promoting thrombus. The overall effect was thus a lack of change in neointimal growth. On the other hand, in Carmeliet's earlier study [32], the excessively high PAI-1 levels following adenoviral gene transfer may have shifted the balance towards a net inhibition of SMC migration, particularly if the amount of intraluminal thrombus was smaller. Another possible limitation is that the time chosen by Lijnen et al. for the assessment of neointimal growth (2 weeks) may have been too short to detect significant differences between the genotypes [7]. In fact, several investigators have shown that, in the mouse, the vascular remodeling process may not be complete until 3 weeks or even longer after injury [1, 32]. Finally, before extrapolating the experimental results to human atherosclerosis and restenosis, it needs to be emphasized that these processes exhibit several histomorphological differences, and that current animal models of arterial injury can only partly reproduce the pathophysiology of either condition. At present, we have to admit that we are still far from a unifying theory to explain the entire spectrum of the effects of PAI-1 on vasculopathy. It has been proposed that the overall effect of the inhibitor may be the destabilization and rupture of atherosclerotic plaques by reducing the SMC content while promoting inflammation and thrombosis in the vessel wall [9]. Although this is an appealing hypothesis, direct proof is lacking. Thus, despite the available clinical and experimental evidence supporting a role of PAI-1 in cardiovascular disease and the acute coronary syndromes, further data are needed to determine whether altering the vascular expression and the systemic levels of the inhibitor can become a useful strategy for reducing the risk of myocardial infarction and/or restenosis after angioplasty." @default.
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• W2016031258 title "PAI‐1 and vasculopathy: the debate continues" @default.
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