Transforming growth factor-beta1 (TGF-β1) may participate in local chronic inflammatory processes in varicose veins and in venous wall structure modifications through regulation of matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitor of metalloproteinase (TIMP)). The aim of this study was to analyze the effect of TGF-β1 in the vein wall, namely on the gene expression of selected MMP, TIMP and TGF-β1 receptors.
Methods
Healthy vein samples were harvested from eight subjects who underwent coronary bypass graft surgery with great saphenous vein. Each vein sample was divided into two segments, which were cultivated separately in vitro (one of the segments had TGF-β1 added) and then submitted to gene expression analysis.
Results
In the TGF-β1 supplemented group, there was a general increase in the mean gene expression. Specifically, expression of MMP9, MMP12, TIMP1 and TIMP2 were statistically significant.
Conclusion
The results of this study demonstrate that the gene expression of MMP9, MMP12, TIMP1 and TIMP2 was influenced by the addition of TGF-β1. These results may be translated to chronic venous insufficiency framework and suggest involvement of TGF-β1 in the vein wall pathology.
Da SilvaANavarroMFBatalheiroJ. [The importance of chronic venous insufficiency. Various preliminary data on its medico-social consequences]. Phlebologie1992; 45: 439–443.
3.
BerganJ. Molecular mechanisms in chronic venous insufficiency. Ann Vasc Surg2007; 21: 260–266.
4.
PascarellaLSchmid-SchonbeinGWBerganJ. An animal model of venous hypertension: the role of inflammation in venous valve failure. J Vasc Surg2005; 41: 303–311.
5.
SaharayMShieldsDAGeorgiannosSN. Endothelial activation in patients with chronic venous disease. Eur J Vasc Endovasc Surg1998; 15: 342–349.
6.
SaitoSTrovatoMJYouR. Role of matrix metalloproteinases 1, 2, and 9 and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufficiency. J Vasc Surg2001; 34: 930–938.
WoodsideKJHuMBurkeA. Morphologic characteristics of varicose veins: possible role of metalloproteinases. J Vasc Surg2003; 38: 162–169.
9.
OverallCMWranaJLSodekJ. Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. J Biol Chem1989; 264: 1860–1869.
10.
VisseRNagaseH. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res2003; 92: 827–839.
11.
PappasPJYouRRameshwarP. Dermal tissue fibrosis in patients with chronic venous insufficiency is associated with increased transforming growth factor-beta1 gene expression and protein production. J Vasc Surg1999; 30: 1129–1145.
12.
GoumansMJLiuZten DijkeP. TGF-beta signaling in vascular biology and dysfunction. Cell Res2009; 19: 116–127.
13.
KowalewskiRMalkowskiAGackoM. Influence of thrombophlebitis on TGF-beta1 and its signaling pathway in the vein wall. Folia Histochem Cytobiol2010; 48: 542–548.
14.
Ruiz-OrtegaMRodriguez-VitaJSanchez-LopezE. TGF-beta signaling in vascular fibrosis. Cardiovasc Res2007; 74: 196–206.
15.
EtonDTerramaniTTWangY. Genetic engineering of stent grafts with a highly efficient pseudotyped retroviral vector. J Vasc Surg1999; 29: 863–873.
16.
YuHKumarSRTangL. Injury induced neointima formation and its inhibition by retrovirus-mediated transfer of nitride oxide synthase gene in an in-vitro human saphenous vein culture model. Atherosclerosis2002; 161: 113–122.
17.
BrandlAAngelePRollC. Influence of the growth factors PDGF-BB, TGF-beta1 and bFGF on the replicative aging of human articular chondrocytes during in vitro expansion. J Orthop Res2010; 28: 354–360.
18.
PoleniPEEtienneSVelotE. Activation of PPARs alpha, beta/delta, and gamma impairs TGF-beta1-induced collagens' production and modulates the TIMP-1/MMPs balance in three-dimensional cultured chondrocytes. PPAR Res –2010. 2010: 635912.
19.
TezcanBSerterSKiterE. Dose dependent effect of C-type natriuretic peptide signaling in glycosaminoglycan synthesis during TGF-beta1 induced chondrogenic differentiation of mesenchymal stem cells. J Mol Histol2010; 41: 247–258.
20.
WilliamsGMDillsKJFloresCR. Differential regulation of immature articular cartilage compressive moduli and Poisson's ratios by in vitro stimulation with IGF-1 and TGF-beta1. J Biomech2010; 43: 2501–2507.
21.
PfafflMWLangeIGDaxenbergerA. Tissue-specific expression pattern of estrogen receptors (ER): quantification of ER alpha and ER beta mRNA with real-time RT-PCR. APMIS2001; 109: 345–355.
SerraRBuffoneGCostanzoG. Altered metalloproteinase-9 expression as least common denominator between varicocele, inguinal hernia, and chronic venous disorders. Ann Vasc Surg2014; 28: 705–709.
24.
SerraRGallelliLGrandeR. Hemorrhoids and matrix metalloproteinases: A multicenter study on the predictive role of biomarkers. Surgery2016; 159: 487–494.
25.
de FranciscisSGallelliLAmatoB. Plasma MMP and TIMP evaluation in patients with deep venous thrombosis: could they have a predictive role in the development of post-thrombotic syndrome?Int Wound J–2015. DOI: 10.1111/iwj.12489.
26.
de FranciscisSSerraR. Matrix metalloproteinases and endothelial dysfunction: The search for new prognostic markers and for new therapeutic targets for vascular wall imbalance. Thromb Res2015; 136: 5–6.
27.
AmatoBCorettiGCompagnaR. Role of matrix metalloproteinases in non-healing venous ulcers. Int Wound J2015; 12: 641–645.
28.
EdwardsDRMurphyGReynoldsJJ. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J1987; 6: 1899–1904.
29.
EstevePOTremblayPHoudeM. In vitro expression of MMP-2 and MMP-9 in glioma cells following exposure to inflammatory mediators. Biochim Biophys Acta1998; 1403: 85–96.
30.
ItohHKishoreAHLindqvistA. Transforming growth factor beta1 (TGFbeta1) and progesterone regulate matrix metalloproteinases (MMP) in human endometrial stromal cells. J Clin Endocrin Metab2012; 97: E888–E897.
31.
JacobTHingoraniAAscherE. Overexpression of transforming growth factor-beta1 correlates with increased synthesis of nitric oxide synthase in varicose veins. J Vasc Surg2005; 41: 523–530.
32.
KobayashiTKimHLiuX. Matrix metalloproteinase-9 activates TGF-beta and stimulates fibroblast contraction of collagen gels. Am J Physiol Lung Cell Mol Physiol2014; 306: L1006–L1015.
33.
LeaskAAbrahamDJ. TGF-beta signaling and the fibrotic response. FASEB J2004; 18: 816–827.
34.
MartiHPLeeLKashgarianM. Transforming growth factor-beta 1 stimulates glomerular mesangial cell synthesis of the 72-kd type IV collagenase. Am J Pathol1994; 144: 82–94.
35.
NicolaidesAN. Chronic venous disease and the leukocyte-endothelium interaction: from symptoms to ulceration. Angiology2005; 56(Suppl 1): S11–S19.
36.
PascualGMendietaCGarcia-HonduvillaN. TGF-beta1 upregulation in the aging varicose vein. J Vasc Res2007; 44: 192–201.
37.
RenJGChenGZhuJY. Downregulation of the transforming growth factor-beta/connective tissue growth factor 2 signalling pathway in venous malformations: its target potential for sclerotherapy. Br J Dermatol2014; 171: 242–251.
38.
RizziECeronCSGuimaraesDA. Temporal changes in cardiac matrix metalloproteinase activity, oxidative stress, and TGF-beta in renovascular hypertension-induced cardiac hypertrophy. Exp Mol Pathol2013; 94: 1–9.
39.
Schmid-SchonbeinGWTakaseSBerganJJ. New advances in the understanding of the pathophysiology of chronic venous insufficiency. Angiology2001; 52(Suppl 1): S27–S34.
40.
VerrecchiaFMauvielA. Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol2002; 118: 211–215.
41.
ZhangHWangZWWuHB. Transforming growth factor-beta1 induces matrix metalloproteinase-9 expression in rat vascular smooth muscle cells via ROS-dependent ERK-NF-kappaB pathways. Mol Cell Biochem2013; 375: 11–21.
42.
Badier-CommanderCVerbeurenTLebardC. Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation. J Pathol2000; 192: 105–112.
43.
GillespieDLPatelAFiletaB. Varicose veins possess greater quantities of MMP-1 than normal veins and demonstrate regional variation in MMP-1 and MMP-13. J Surg Res2002; 106: 233–238.
44.
IshikawaYAsuwaNIshiiT. Collagen alteration in vascular remodeling by hemodynamic factors. Virchows Archiv2000; 437: 138–148.
45.
JacobMPCazaubonMScemamaA. Plasma matrix metalloproteinase-9 as a marker of blood stasis in varicose veins. Circulation2002; 106: 535–538.
46.
KosugiIUrayamaHKasashimaF. Matrix metalloproteinase-9 and urokinase-type plasminogen activator in varicose veins. Ann Vasc Surg2003; 17: 234–238.
47.
KowalewskiRSobolewskiKWolanskaM. Matrix metalloproteinases in the vein wall. Int Angiol2004; 23: 164–169.
48.
ParraJRCambriaRAHowerCD. Tissue inhibitor of metalloproteinase-1 is increased in the saphenofemoral junction of patients with varices in the leg. J Vasc Surg1998; 28: 669–675.
49.
Sansilvestri-MorelPFiorettiFRupinA. Comparison of extracellular matrix in skin and saphenous veins from patients with varicose veins: does the skin reflect venous matrix changes?Clin Sci2007; 112: 229–239.
50.
Sansilvestri-MorelPNonotteIFournet-BourguignonMP. Abnormal deposition of extracellular matrix proteins by cultured smooth muscle cells from human varicose veins. J Vasc Res1998; 35: 115–123.
51.
Sansilvestri-MorelPRupinAJullienND. Decreased production of collagen Type III in cultured smooth muscle cells from varicose vein patients is due to a degradation by MMPs: possible implication of MMP-3. J Vasc Res2005; 42: 388–398.
