Veränderungen der extrazellulären Matrix in der Venenwand – Ursache der primären Varikosis?

Kirsch, D.; Dienes, Hans‐Peter; Küchle, R.; Duschner, H.; Wahl, W.; Böttger, Th.; Junginger, T

doi:10.1024/0301-1526.29.3.173

Cited by 35 publications

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“…Several experimental and clinical studies suggest that defects in the venous wall may be regarded as the primary cause of varicosis leading to secondary valvular incompetence [4, 5]. Modifications in the media layer of the venous wall appear as general features of varicose veins.…”

Section: Introductionmentioning

confidence: 99%

Identification of Differentially Expressed Genes in Human Varicose Veins: Involvement of Matrix Gla Protein in Extracellular Matrix Remodeling

et al. 2007

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This study was designed to identify the global pattern of differentially expressed genes in human varicose veins. Using suppressive subtractive hybridization, we identified overexpression of genes known to be associated with extracellular matrix remodeling, including collagen III, tissue inhibitor of metalloproteinases I, dermatopontin, matrix Gla protein (MGP) and tenascin C. Real-time polymerase chain reaction analysis confirmed the differential expression of these genes. The overexpression of MGP transcript was associated with increased MGP level in varicose veins, in particular the undercarboxylated form of the protein. Smooth muscle cells from varicose veins showed increased proliferation rate and enhanced matrix mineralization. This observation correlated with the presence of ectopic mineralization areas in the varicose vein walls. The use of warfarin, to inhibit MGP activity, or siRNA targeting MGP transcript induced a reduction in the exacerbated proliferation of varicose vein smooth muscle cells. Our results suggest that high expression of MGP in varicose veins may contribute to venous wall remodeling by affecting proliferation and mineralization processes probably through impaired carboxylation of MGP. In addition, suppressive subtractive hybridization results also produce a profile of differentially expressed genes in varicose veins, in particular extracellular matrix components. Further study of these genes will provide insights into their specific roles in the etiology of venous disease.

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Section: Introductionmentioning

confidence: 99%

Identification of Differentially Expressed Genes in Human Varicose Veins: Involvement of Matrix Gla Protein in Extracellular Matrix Remodeling

et al. 2007

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“…Different studies have shown that an abnormal remodeling occurs in varicose veins [1,2,3] and these alterations of the venous wall may be regarded as the primary cause of varicosis [4, 5]. Dilatations occur because the venous wall is weakened and valvular incompetence is secondary rather than primary [4].…”

Section: Introductionmentioning

confidence: 99%

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

Sansilvestri-Morel

Rupin²,

Jullien³

et al. 2005

J Vasc Res

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An alteration of extracellular matrix is involved in varicose veins. We have previously shown that collagen III production, but not its mRNA expression, is decreased in cultured smooth muscle cells (SMC) from varicose veins, involving an over-production of collagen I. In this study, the mechanisms involved in this collagen III reduction are explored. Steady state levels of collagen III mRNA and its ability to translate a protein were evaluated. Neither stability nor functionality of the α1(III) coding mRNA were affected in cells from varicose veins. Potential intracellular degradations of collagen III were investigated with inhibitors of intracellular proteases but the production was unaffected. The level of N-terminal propeptides of collagen III in the extracellular medium was determined and was similar in SMC from control and varicose veins. The stability of collagen III was determined by time-course experiments and a degradation of the protein was observed in cells from varicose veins. The production of collagen III was partially restored in cells from varicose veins in the presence of Marimastat, a matrix metalloproteinase (MMP) inhibitor. The mRNA expression and protein production of MMP3 were increased in cells from varicose veins. Fibronectin, a potential substrate of MMP3, was decreased in SMC from varicose veins. In conclusion, collagen III, and probably fibronectin, are degraded extracellularly in SMC from varicose veins by a mechanism involving MMPs, and maybe MMP3 by a direct or an indirect pathway. The degradation of collagen III and fibronectin may have repercussions for the mechanical properties of the venous wall.

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“…52 Also, biochemical abnormalities similar to those observed in varicose veins have been demonstrated in normal-appearing human saphenous vein wall adjacent to varicose veins and between competent venous valves. 55, 56 We have also shown that prolonged increases in vein wall tension in rat IVC is associated with venous dysfunction and decreased vein contraction. 27 The increased vein wall tension causes an increase in matrix metalloproteinases MMP-2 and MMP-9, and MMPs in turn cause vein wall hyperpolarization and venous relaxation possibly by activating large conductance Ca 2+ dependent K + channels.…”

Section: Discussionmentioning

confidence: 79%

Endothelium-dependent nitric oxide and hyperpolarization-mediated venous relaxation pathways in rat inferior vena cava

Raffetto

Reslan

et al. 2012

Journal of Vascular Surgery

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Introduction The vascular endothelium plays a major role in the control of arterial tone; however, its role in venous tissues is less clear. The purpose of this study was to determine the role of endothelium in the control of venous function, and the relaxation pathways involved. Methods Circular segments of inferior vena cava (IVC) from male Sprague-Dawley rats were suspended between two wires and isometric contraction to phenylephrine (Phe, 10−5M) and 96 mM KCl was measured. Acetylcholine (Ach, 10−10 to 10−5M) was added and the percentage venous relaxation was measured. To determine the role of nitric oxide (NO) and prostacyclin (PGI2), vein relaxation was measured in the presence of the NOS inhibitor L-NAME (3X10−4 M) and the COX inhibitor indomethacin (10−5 M). To measure the role of hyperpolarization, vein relaxation was measured in the presence of K+ channel activator cromakalim (10−11 to 10−6 M), and the nonselective K+ channel blocker tetraethylammonium (TEA, 10−3 M). To test for the contribution of a specific K+ channel, the effects of K+ channel blockers: glibenclamide (ATP-sensitive KATP, 10−5M), 4-aminopyridine (4-AP, voltage-dependent Kv, 10−3M), apamin (small conductance Ca2+-dependent SKCa, 10−7M), and iberiotoxin (large conductance Ca2+-dependent BKCa, 10−8M), on Ach-induced relaxation were tested. Results Ach caused concentration-dependent relaxation of Phe contraction (max 49.9±4.9%). Removal of endothelium abolished Ach-induced relaxation. IVC treatment with L-NAME partially reduced Ach relaxation (32.8±4.9%). In IVC treated with L-NAME plus indomethacin significant Ach-induced relaxation (33.6±3.2%) could still be observed, suggesting a role of endothelium-derived hyperpolarizing factor (EDHF). In IVC treated with L-NAME, indomethacin and TEA, Ach relaxation was abolished, supporting a role of EDHF. In veins stimulated with high KCl, Ach caused relaxation (max 59.5±3.5%) that was abolished in the presence of L-NAME and indomethacin suggesting that any Ach-induced EDHF is blocked in the presence of high KCl depolarizing solution, which does not favor outward movement of K+ ion and membrane hyperpolarization. Cromakalim, activator of KATP, caused significant IVC relaxation when applied alone or on top of maximal Ach-induced relaxation, suggesting that the Ach response may not involve KATP. Ach-induced relaxation was not inhibited by glibenclamide, 4-AP or apamin, suggesting little role of KATP, Kv or SKCa, respectively. In contrast, iberiotoxin significantly inhibited Ach-induced relaxation, suggesting a role of BKCa. Conclusions Thus endothelium-dependent venous relaxation plays a major role in the control of venous function. In addition to NO, an EDHF pathway involving BKCa may play a role in endothelium-dependent venous relaxation.

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Veränderungen der extrazellulären Matrix in der Venenwand – Ursache der primären Varikosis?

Abstract: If the findings of the present investigation can be confirmed by other studies, alterations in the vein wall may be regarded as the primary cause of varicosis and valvular insufficiency as the result of these changes.

Cited by 35 publications

References 0 publications

Identification of Differentially Expressed Genes in Human Varicose Veins: Involvement of Matrix Gla Protein in Extracellular Matrix Remodeling

Identification of Differentially Expressed Genes in Human Varicose Veins: Involvement of Matrix Gla Protein in Extracellular Matrix Remodeling

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

Endothelium-dependent nitric oxide and hyperpolarization-mediated venous relaxation pathways in rat inferior vena cava

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