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Upregulation of Plasminogen Activator Inhibitor-1 in Irradiated Recipient Arteries and Veins from Fre 时间:2018-10-08 09:34 来源:未知作者:admin 点击: 次 Abstract:Background. Clinical studies have shown that radiotherapy can induce vascular disease at the site of exposure but is usually not clinically evident until years after treatment. We have studied irradiated human arteries and veins to better understand the underlying biology in search of future treatments. The aim was to investigate whether radiotherapy contributed to a sustained expression of plasminogen activator inhibitor-1 (PAI-1) in human arteries and veins. Methods. Irradiated arteries and veins were harvested, together with unirradiated control vessels, from patients undergoing free tissue transfer reconstruction at a median time of 90 weeks [5–650] following radiation exposure. Differential gene expression of PAI-1 was analysed, together with immunohistochemistry (IHC) and immunofluorescence (IF). Results. PAI-1 gene expression was increased in both arteries () and veins () in irradiated compared to unirradiated control vessels. IHC and IF indicated that cells expressing PAI-1 were located in the adventitia of both arteries and veins and colocalized with cells positive for CD68, CD45, and α-SMA in arteries and with CD45 and α-SMA in veins. Conclusion. The current study shows a sustained upregulation of PAI-1 in both arteries and veins after exposure to ionizing radiation, indicating a chronic inflammation mainly in the adventitia. We believe that the results contribute to further understanding of radiation-induced vascular disease, where targeting PAI-1 may be a potential treatment.
1. Introduction
Radiotherapy, a cornerstone in the treatment of patients with cancer, inevitably involves exposing healthy, surrounding tissue to ionizing radiation. Better overall treatment has led to an increasing number of cancer survivors and consequently more patients suffering from late adverse effects. Recent epidemiological studies have shown that localized cardiovascular disease may occur at the site of exposure, e.g., myocardial infarction or stroke after thorax or neck irradiation, respectively [1–6]. One theory of mechanisms of late vascular morbidity after radiotherapy is that oxidative stress leads to sustained inflammation of blood vessel walls, which is suspected to contribute to the development of atherosclerosis and subsequent thromboembolic events [5, 7, 8]. Previous studies have shown an activation of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) inflammatory pathway in irradiated arteries [9] and sustained expression of plasminogen activator inhibitor-1 (PAI-1), a downstream mediator in the NF-κB cascade, in irradiated veins [10]. This may be of relevance for an increased risk of vascular occlusions observed in free-flap reconstructions after radiotherapy [11]. Surgery in previously irradiated patients can furthermore lead to a higher incidence of early and late posttherapeutic complications [12, 13], possibly related to detrimental effects of radiotherapy on the endothelium [14, 15]. PAI-1 has been linked to thrombus formation in the microcirculatory bed [16], which might be a mechanism contributing to general surgical complications as well as flap bed-related complications in the reconstructive setting [10].
The aim of the current study was to corroborate previous evidence of an elevated expression of PAI-1 in previously irradiated arteries and veins by the analysis of the more endothelium-specific Serpine1, instead of Serpine2. By including both arteries and veins in the same analysis, we aimed to gain insight into differences between the respective vessel types and furthermore describe the morphology of PAI-1 expression within the vessel wall, which, to our knowledge, has never previously been described in humans.