Increased vascular endothelial growth factor may account for elevated level of plasminogen activator inhibitor-1 via activating ERK1/2 in keloid fibroblasts
Increased vascular endothelial growth factor may account for elevated level of plasminogen activator inhibitor-1 via activating ERK1/2 in keloid fibroblasts
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DOI：
10.1152/ajpcell.00200.2003
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发表时间：
2004-04-01
影响因子：
5.5
通讯作者：
Le, AD
中科院分区：
文献类型：
--
作者：
Wu, YD;Zhang, QZ;Le, AD
瘢痕疙瘩的特征在于“过度兴奋”愈合反应，其中细胞外基质（ECM）的产生和释放之间发生不平衡。我们实验室和其他实验室的先前研究表明，与正常皮肤相比，瘢痕疙瘩组织和培养的成纤维细胞中纤溶酶原激活物抑制剂-1（派-1）的表达水平本质上更高。这些发现支持了纤溶酶原系统中激活剂和抑制剂活性平衡改变的概念，特别是派-1的过表达，可能部分导致瘢痕疙瘩形成和组织纤维化。血管内皮生长因子（VEGF）是调节血管生成和炎症的重要因子。本研究旨在评估VEGF是否在瘢痕疙瘩纤维化中发挥作用。我们报告称，与相关的正常皮肤相比，瘢痕疙瘩组织及其衍生的成纤维细胞中VEGF的表达水平更高。我们已经进一步证明，VEGF刺激派-1的表达，但不是尿激酶纤溶酶原激活剂（uPA），在瘢痕疙瘩成纤维细胞在mRNA和蛋白水平，在剂量和时间依赖性的方式。然而，正常皮肤成纤维细胞与VEGF治疗派-1基因表达的影响不大。此外，我们首次发现细胞外信号调节激酶（ERK）1/2信号通路主要参与VEGF诱导的派-1表达，并证明其作为调节瘢痕纤维化的靶分子的潜力。这些发现表明，VEGF可能通过改变ECM稳态向受损的降解和过度积累的状态在瘢痕疙瘩形成中发挥重要作用。
Keloids are characterized as an "overexuberant" healing response in which disequilibrium between production and catabolism of extracellular matrix (ECM) occurs. Previous studies from our laboratory and others demonstrate an intrinsically higher level of plasminogen activator inhibitor-1 (PAI-1) expression in keloid tissues and cultured fibroblasts compared with normal bordering skin. These findings support the concept that an altered balance of activator and inhibitor activities in the plasminogen system, in particular, an overexpression of PAI-1, may partly contribute to keloid formation and tissue fibrosis. Vascular endothelial growth factor (VEGF) has been implicated as a critical factor in regulating angiogenesis and inflammation under both physiological and pathological conditions. This study was designed to assess whether VEGF plays a role in keloid fibrosis. We report that VEGF was expressed at higher levels in keloid tissues and their derived fibroblasts compared with their associated normal skin. We have further demonstrated that VEGF stimulated the expression of PAI-1, but not urokinase plasminogen activator (uPA), in keloid fibroblasts at both mRNA and protein levels, in a dose- and time-dependent manner. However, treatment of normal skin fibroblasts with VEGF exerted little effects on PAI-1 gene expression. Additionally, we have characterized for the first time that the extracellular signal-regulated kinase (ERK)1/2 signaling pathway is mainly involved in VEGF-induced PAI-1 expression and have demonstrated its potential as a target molecule for modulation of scar fibrosis. These findings suggest that VEGF may play an important role in keloid formation by altering ECM homeostasis toward a state of impaired degradation and excessive accumulation.