Abstract
Chronic venous disease (CVeD) is a prevalent condition with a significant socioeconomic burden, yet the pathophysiology is only just beginning to be understood. Previous studies concerning the dysregulation of matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases (TIMPs)) within the varicose vein wall are inconsistent and disregard clinical progression. Moreover, it is highly plausible that MMP and TIMP expression/activity is affected by transforming growth factor (TGF)-β1 and its signaling receptors (TGFβRs) expression/activity in the vein wall. A case–control study was undertaken to analyze genetic and immunohistochemical differences between healthy (n = 13) and CVeD (early stages: n = 19; advanced stages: n = 12) great saphenous vein samples. Samples were grouped based on anatomic harvest site and subjected to quantitative polymerase chain reaction for MMP1, MMP2, MMP8, MMP9, MMP12, MMP13, TIMP1, TIMP2, TIMP3, TIMP4, TGFβR1, TGFβR2, and TGFβR3 gene expression analysis, and then to immunohistochemistry for immunolocalization of MMP2, TIMP2, and TGFβR2. Decreased gene expression of MMP12, TIMP2, TIMP3, TIMP4, and TGFβR2 was found in varicose veins when compared to controls. Regarding CVeD clinical progression, two facts arose: results across anatomical regions were uneven; decreased gene expression of MMP9 and TGFβR3 and increased gene expression of MMP2 and TIMP3 were found in advanced clinical stages. Most immunohistochemistry results for tunica intima were coherent with qPCR results. In conclusion, decreased expression of TGFβRs might suggest a reduction in TGF-β1 participation in the MMP/TIMP imbalance throughout CVeD progression. Further studies about molecular events in the varicose vein wall are required and should take into consideration the venous anatomical region and CVeD clinical progression.
Highlights
Matrix metalloproteinases (MMPs) are a large family of endopeptidases that are secreted in their latent form by different cells in the venous wall and have proteolytic activities that participate in cellular homeostasis, adaptation, and tissue remodeling [1,2,3]
We have previously demonstrated that transforming growth factor (TGF)-β1 may directly intervene in the gene expression of MMP/TIMP in the great saphenous vein wall [30], which reinforced the hypothesis that the inflammatory process may lead to morphologic changes within the vein wall that is mediated by MMP and TIMP expression/activity [8,12,31]
The choice of specific MMPs was based on previously published studies [29], yet only genetic data concerning MMP2, MMP9, MMP12, TIMP1, TIMP2, TIMP3, TIMP4, TGFβR2, and TGFβR3 are discussed as RT-polymerase chain reactions (PCR) results showed no detection of MMP8 and MMP13 gene expression
Summary
Matrix metalloproteinases (MMPs) are a large family of endopeptidases that are secreted in their latent form by different cells in the venous wall (including fibroblasts, vascular smooth muscle cells, and leukocytes) and have proteolytic activities that participate in cellular homeostasis, adaptation, and tissue remodeling [1,2,3]. Transforming growth factor β (TGF-β) is a multifunctional growth factor that is widely expressed in diverse tissues, and which has critical and specific roles during embryogenesis and in maintaining the homeostasis of adult tissues [5]. This growth factor has three different isoforms in mammals (TGFβ1–3) [5,6]. TGF-β1 access to the signaling receptors is regulated by membrane-associated coreceptors (e.g., TGFβR3) that are thought to not signal directly [5,10]
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