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      TGF-beta1 upregulation in the aging varicose vein.

      Journal of Vascular Research
      Adult, Aged, Aged, 80 and over, Aging, metabolism, pathology, Blotting, Western, Cell Degranulation, Cells, Cultured, Chronic Disease, Female, Humans, Immunohistochemistry, Male, Mast Cells, Middle Aged, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Saphenous Vein, Transforming Growth Factor beta1, biosynthesis, Up-Regulation, Varicose Veins, Venous Insufficiency

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          Abstract

          Although the etiology of venous insufficiency is not well understood, immune response and aging are beginning to emerge as contributing factors. Factors involved in tissue remodeling such as TGF-beta(1) also seem to play an important role in extracellular matrix production. The aim of this study was to explore the relationship between chronic venous insufficiency and TGF-beta(1) examining the latent/mature form of TGF-beta(1) and the presence of mast cells. Effects of age were also evaluated. Saphenous veins were obtained from patients subjected to aortocoronary bypass (controls) and undergoing varicose vein surgery. These were immunolabeled using anti-LAP TGF-beta(1)/anti-TGF-beta(1) antibodies and subjected to Western blot. Mast cell population was identified by metachromatic staining. Latent TGF-beta(1) was significantly reduced in varicose veins from older subjects. In contrast, smooth muscle cells obtained from the varicosities showed intense levels. Mature TGF-beta(1) significantly differed between healthy and varicose veins. No mature TGF-beta(1) was detected in the cell cultures. Mast cell number and degranulation were increased with aging and varicose disease, colocalizing with the mature form of TGF-beta(1). Aging and varicose pathology induce dysregulation of TGF-beta(1) that could play an important role in the fibrous process, representing the final stages of venous insufficiency.

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          Most cited references21

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          Metalloproteinases and their inhibitors in matrix remodeling.

          The matrix metalloproteinases are a tightly regulated family of enzymes that degrade extracellular matrix and basement membrane components. Recent evidence suggests that these proteases and their specific inhibitors play important roles in normal developmental processes and in pathological conditions. Interestingly, experiments designed to improve our understanding of metalloproteinase regulation have also resulted in new insights into mechanisms by which growth factors and proto-oncogenes may regulate biological processes.
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            Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability.

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              Production of transforming growth factor beta 1 during repair of arterial injury.

              Repair of arterial injury produced by balloon angioplasty leads to the formation of a neointima and a narrowing of the vascular lumen. In this study, we examined the possibility that smooth muscle cells (SMC) in injured rat carotid arteries are stimulated to produce type-1 transforming growth factor-beta (TGF-beta 1) during neointima formation in vivo. Levels of TGF-beta 1 transcripts (2.4 kb) were significantly increased within 6 h after carotid injury and reached a maximum (five to sevenfold) by 24 h. Regenerating left carotids had sustained increases in TGF-beta 1 mRNA levels (about fivefold) over the next 2 wk, during which time a substantial neointimal thickening was formed. No changes in basal TGF-beta 1 mRNA levels were found in contralateral uninjured carotids at any of the times examined. Immunohistochemical studies showed that a large majority of neointimal SMC were stained for TGF-beta 1 protein in an intracellular pattern, consistent with active TGF-beta 1 synthesis in this tissue. Neointima formation and TGF-beta 1 immunoreactivity were correlated with increases in fibronectin, collagen alpha 2(I), and collagen alpha 1(III) gene expression. Infusion of purified, recombinant TGF-beta 1 into rats with a preexisting neointima produced a significant stimulation of carotid neointimal SMC DNA synthesis. These results suggest that TGF-beta 1 plays an important role as an endogenous growth regulatory factor produced by neointimal SMC themselves during progressive neointimal thickening after balloon angioplasty.
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