Effect of TGF-beta1 on MMP/TIMP and TGF-beta1 receptors in great saphenous veins and its significance on chronic venous insufficiency

Serralheiro, Pedro; Cairrão, Elisa; Maia, Cláudio J.; João, Marina Delgado; Almeida, Carlos M. Costa; Verde, Ignácio

doi:10.1177/0268355516655067

Cited by 19 publications

(18 citation statements)

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“…We have previously demonstrated that 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 ]. Increasing knowledge about TGF-β1 signaling mechanisms and regulation indicates that signaling responses are extensively defined by TGF-β1 receptor availability and function [ 10 , 32 ].…”

Section: Introductionmentioning

confidence: 79%

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

Serralheiro

Novais

Cairrão

et al. 2017

IJMS

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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.

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Section: Introductionmentioning

confidence: 79%

“…For complementary deoxyribonucleic acid (cDNA) synthesis, 500 ng of total RNA was reverse transcribed using the M-MuLV Reverse Transcriptase kit (NZYTech ® , Lisbon, Portugal) in a final volume of 20 mL. Both procedures have been described elsewhere [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

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

Serralheiro

Novais

Cairrão

et al. 2017

IJMS

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“…Depletion of vein elastic components is a common observation in the venous wall of elderly and CVI patients (particularly, during the disease later stages) [ 116 , 127 ] that was related to decreased elastin synthesis and increased elastase activity, which in turn could be a consequence of elastic tissue modulators (such as LTBP and TGF-β1) attempt to stabilize elastin expression in regions of extensive injury [ 116 ]. In addition, some authors suggested that abnormalities in ECM structure leading to decreased elasticity and increased distensibility of the venous wall result from an imbalance between MMP (endopeptidases involved in the degradation of several ECM proteins) and TIMP (their endogenous inhibitors) [ 12 , 15 , 16 , 18 , 112 , 128 ], which are regulated at both transcriptional and post-transcriptional levels by various cytokines or growth factors, including TGF-β1 [ 15 , 118 ] ( Figure 4 ). In reverse, MMP upregulation may also promote growth factor release (by cleaving growth factor-binding proteins) and this may partly explain the VSMC hypertrophy observed in some parts of the hypertrophic regions of varicose veins [ 18 ].…”

Section: The Role Of Tgf-β1 Signaling Pathways In Vessel Wall Pathmentioning

confidence: 99%

TGF-β1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology

Serralheiro

Soares

Almeida

et al. 2017

IJMS

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Chronic venous insufficiency and varicose veins occur commonly in affluent countries and are a socioeconomic burden. However, there remains a relative lack of knowledge about venous pathophysiology. Various theories have been suggested, yet the molecular sequence of events is poorly understood. Transforming growth factor-beta one (TGF-β1) is a highly complex polypeptide with multifunctional properties that has an active role during embryonic development, in adult organ physiology and in the pathophysiology of major diseases, including cancer and various autoimmune, fibrotic and cardiovascular diseases. Therefore, an emphasis on understanding its signaling pathways (and possible disruptions) will be an essential requirement for a better comprehension and management of specific diseases. This review aims at shedding more light on venous pathophysiology by describing the TGF-β1 structure, function, activation and signaling, and providing an overview of how this growth factor and disturbances in its signaling pathway may contribute to specific pathological processes concerning the vessel wall which, in turn, may have a role in chronic venous insufficiency.

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“…Decreasing the amount of active TGFβ causes smooth muscle cells to undergo apoptosis, but adding exogenous TGFβ has no benefi cial eff ect [37], while gene expression of MMP9, MMP12, TIMP1 and TIMP2 is infl uenced by the addition of TGF-β1. Th ese results may be translated to chronic venous insuffi ciency framework and suggest involvement of TGF-β1 in the vein wall pathology [38].…”

Section: Discussionmentioning

confidence: 85%

Characterisation of blood vessels used for coronary artery bypass surgery

Garnizone

Vārtiņa

Pilmane

2019

PoA

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Saphenous veins are commonly used as coronary artery bypass grafts. Therefore, it is important to understand the vein wall morphology used for the bypass grafts. Methods. Ten specimens of saphenous veins were obtained from 10 patients admitted to the Heart Surgery Centre of P. Stradiņš Clinical University Hospital for coronary artery bypass surgery and a histopathological study was conducted. The slides were processed for histological routine and immunohistochemical staining with following markers: endothelin (ET), metallomembranoproteinase 2 (MMP2), tissue inhibitor of metalloproteinase 2 (TIMP2), transforming growth factor beta (TGF β), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), protein gene product 9.5 (PGP9.5), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM). For the analysis of the positive structures detected by immunohistochemistry, a semiquantitative evaluation method was used. Results. Normal histoarchitecture of the vein wall was evaluated by routine staining. Moderate positive endothelin containing endothelial cells and moderate to numerous positive VEGF cells were found on small blood vessels. Moderate positive MMP2 structures and variable – mainly moderate to numerous positive TIMP structures – were found in vein wall. Positive structures were evaluated as equal with both MMP2 and TIMP, with one exception where MMP2 positive structures were evaluated as moderate, but TIMP positive structures as few. All specimens were rich in TGFβ, VCAM and ICAM cells. Abundance of VCAM and ICAM positive endothelial cells was also found. Few HGF positive structures were found in tunica intima and few PGP9.5 positive nerve fibres in tunica adventitia. Conclusions. Rich expression of TGFβ, VCAM, ICAM is characteristic for saphenous vein. A number of VEGF, MMP and TIMP positive cells found in saphenous vein wall indicates a presence of tissue remodelling and ischemia, while low number of HGF positive cells shows its lesser involvement in homeostasis regulation.

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Effect of TGF-beta1 on MMP/TIMP and TGF-beta1 receptors in great saphenous veins and its significance on chronic venous insufficiency

Cited by 19 publications

References 50 publications

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

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

TGF-β1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology

Characterisation of blood vessels used for coronary artery bypass surgery

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