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Int. J. Mol. Sci. 2018, 19(1), 6; https://doi.org/10.3390/ijms19010006

Variability of MMP/TIMP and TGF-β1 Receptors throughout the Clinical Progression of Chronic Venous Disease

1
Norfolk and Norwich University Hospital, Norwich NR47UY, UK
2
Faculty of Health Sciences, CICS-UBI—Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal
3
Department of General Surgery (C), Coimbra University Hospital Centre, 3041-801 Coimbra, Portugal
4
Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
*
Author to whom correspondence should be addressed.
Received: 29 November 2017 / Revised: 13 December 2017 / Accepted: 19 December 2017 / Published: 21 December 2017
(This article belongs to the Special Issue Molecular Research on Chronic Venous Disease)
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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. View Full-Text
Keywords: chronic venous disease; matrix metalloproteinases (MMPs); tissue inhibitors of metalloproteinases (TIMPs); transforming growth factor (TGF)-β receptors; varicose vein; gene expression chronic venous disease; matrix metalloproteinases (MMPs); tissue inhibitors of metalloproteinases (TIMPs); transforming growth factor (TGF)-β receptors; varicose vein; gene expression
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Serralheiro, P.; Novais, A.; Cairrão, E.; Maia, C.; Costa Almeida, C.M.; Verde, I. Variability of MMP/TIMP and TGF-β1 Receptors throughout the Clinical Progression of Chronic Venous Disease. Int. J. Mol. Sci. 2018, 19, 6.

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