Assessment of wall structure and composition of varicose veins with reference to collagen, elastin and smooth muscle content

Travers, James; Brookes, C.E.; Evans, J. D.; Baker, DM; Kent, Christine; Makin, G. S.; Mayhew, T.M.

doi:10.1016/s1078-5884(96)80058-x

Cited by 150 publications

(121 citation statements)

References 14 publications

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“…These findings support others, which have shown by combined light and electron microscopy that there are significant alterations of wall morphology at proximal and distal sites, and in different tunics of varicose veins. Varicose veins were also larger with a greater cross sectional areas (and hence volumes) of tunica intima and tunica media (Travers et al, 1996). These changes, however, were not accompanied by changes in the wall thickness, which suggest that in varicosis the dilatation which occurs, is not accompanied by a generalized wall thinning.…”

Section: Discussionmentioning

confidence: 83%

“…Roughly 10% of those affected have complications such as superficial thrombophlebitis, pigmentation, lipodermatosclerosis, hemorrhage, ulceration and increased risk of deep vein thrombosis (Travers et al, 1996). The exact mechanism by which primary varicosis occurs in the lower limb in susceptible individuals has yet to be determined (Clarke et al, 1961).…”

Section: Introductionmentioning

confidence: 99%

“…The exact mechanism by which primary varicosis occurs in the lower limb in susceptible individuals has yet to be determined (Clarke et al, 1961). Heredity is an important factor as more than half of those affected have a positive family history, suggesting a congenital weakness of the vein wall (Travers et al, 1996). The weak wall theory with secondary valvular incompetence has been proposed as the most likely cause of primary varicose veins (Psaila & Melhuish, 1989).…”

Section: Introductionmentioning

confidence: 99%

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Smooth Muscle Changes in Varicose Veins: An Ultrastructural Study

Wali

Eid

2001

J. Smooth Muscle Res.

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In order to understand the pathology of varicose veins, we prospectively collected a total of 23 vein specimens both from the normal proximal thigh long saphenous vein (LSV) in 3 young trauma patients and from the unstripped proximal LSV near the sapheno-femoral junction and the distal calf blowouts in 10 primary varicose veins patients. Ultra-thin sections were examined under the transmission electron microscope (TEM). Compared with the normal control LSV, varicose vein sections showed increase in the diameter of the lumen, hypertrophy of the wall and elongation and invagination of the intima. Smooth muscle cells (SMCS) lost their normal fusiform shape and were widely separated by increased amounts of extra-cellular collagen fibers. The cells underwent marked degeneration, vacuolization and disintegration into fiber-like material and small separated fragments. SMCs were seen in the subintimal tissue and some of them were lost into tile lumen. SMCs also showed marked phagocytic activity, engulfing not only collagen and elastic fibers, but also other smooth muscle cells. Although these changes were more marked and advanced in the distal calf blowouts, they were also present in the proximal, clinically non-dilated LSV. In conclusion, SMCs of varicose veins show severe degeneration in both the distal calf blowouts and the proximal, clinically non-varicose LSV. It appears that they both form and phagocytose collagen and elastic fibers and play a major role in the pathogenesis of varicose veins.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Smooth Muscle Changes in Varicose Veins: An Ultrastructural Study

Wali

Eid

2001

J. Smooth Muscle Res.

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“…This increased thickness could be due to either an increase in SMCs or collagen content of intima. 11 Other intimal changes include folding, invagination, fragmentation, and peeling of intimal endothelium. The infolding of the intimal layer of varicose vein wall results in a neointimal thickened region.…”

Section: Smc Proliferation Was Augmented In Varicose Veins Compared Wmentioning

confidence: 99%

“…13 There are conflicting reports suggesting an increase 14 and a decrease 11,15 of SMCs in varicose veins. In our subjects, we observed a marked increase in SMCs in the varicose vein wall.…”

Section: Smc Proliferation Was Augmented In Varicose Veins Compared Wmentioning

confidence: 99%

Arterialization and anomalous vein wall remodeling in varicose veins is associated with upregulated FoxC2-Dll4 pathway

Sumi

Ramegowda

Suresh

et al. 2016

Laboratory Investigation

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Varicose veins of lower extremities are a heritable common disorder. Mechanisms underlying its pathogenesis are still vague. Structural failures such as valve weakness and wall dilatation in saphenous vein result in venous retrograde flow in lower extremities of body. Reflux of blood leads to distal high venous pressure resulting in distended veins. In an earlier study, we observed a positive association between c.-512C4T FoxC2 gene polymorphism and upregulated FoxC2 expression in varicose vein specimens. FoxC2 overexpression in vitro in venous endothelial cells resulted in the elevated mRNA expression of arterial endothelial markers such as Delta-like ligand 4 (Dll4) and Hairy/enhancer-of-split related with YRPW motif protein 2 (Hey2). We hypothesized that an altered FoxC2-Dll4 signaling underlies saphenous vein wall remodeling in patients with varicose veins. Saphenous veins specimens were collected from 22 patients with varicose veins and 20 control subjects who underwent coronary artery bypass grafting. Tissues were processed for paraffin embedding and sections were immunostained for Dll4, Hey2, EphrinB2, a-SMA, Vimentin, and CD31 antigens and examined under microscope. These observations were confirmed by quantitative real-time PCR and western blot analysis. An examination of varicose vein tissue specimens by immunohistochemistry indicated an elevated expression of Notch pathway components, such as Dll4, Hey2, and EphrinB2, and smooth muscle markers, which was further confirmed by gene and protein expression analyses. We conclude that the molecular alterations in Dll4-Hey2 signaling are associated with smooth muscle cell hypertrophy and hyperplasia in varicose veins. Our observations substantiate a significant role for altered FoxC2-Dll4 signaling in structural alterations of saphenous veins in patients with varicose veins. In conjunction with the presence of genes conferring disease susceptibility, various risk factors, such as prolonged standing, an increased body mass index, and preganancy, increases the mean venous pressure, in the lower extremities. 3,4 Pfisterer et al in 2014 found in an experimental mouse model that an escalated venous filling pressure induces varicose-like venous remodeling. This process to a greater extent mimics detrimental remodeling processes observed in human varicose veins. 5 The precise molecular mechanisms underlying the pathogenesis and progression of varicose veins are unclear. We have earlier observed a significant association of FoxC2 c.-512C4T polymorphism with the presence of varicose veins in patients. FoxC2 was also upregulated at both transcript and protein levels in varicose vein tissues of patients with varicose veins. 6 In venous endothelial cells transfected with FoxC2-overexpressing mammalian vectors, the presence of putative arterial endothelial markers Delta-like ligand 4 (Dll4) and Hairy/enhancer-of-split related with YRPW motif protein 2 (Hey2) were found.

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Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation

Verbeuren²,

et al. 2000

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Primary varicose veins are functionally characterized by venous back-flow and blood stagnation in the upright position. Dilatation and tortuosity provide evidence for progressive venous wall remodelling, with disturbance of smooth muscle cell/extracellular matrix organization. Affected areas are not uniformly distributed, some areas being hypertrophic, whereas others are atrophic or unaffected. In 12 varicose veins and ten control veins, the proteolytic enzyme/inhibitor balance which may participate in the remodelling of the venous wall was investigated. For this purpose, the presence and enzymatic activity of matrix metalloproteinases (MMP-2, MMP-9), tissue inhibitors of MMPs (TIMP-1, TIMP-2), urokinase-type (uPA) and tissue-type (tPA) plasminogen activators (PAs), and plasminogen activator inhibitor-1 (PAI-1) were quantified by western blot and gelatin or plasminogen-casein zymography. In addition, MMP-2, TIMP-1, TIMP-2, and PAI-1 levels were measured by ELISA. A high TIMP-1 level and a low MMP-2 level/activity were found in varicose veins (p<0.005), resulting in a three-fold increase in the TIMP-1/MMP-2 ratio in varicose versus control veins. Levels of PAs (uPA and tPA) as well as PAI-1 were both lower in varicose veins (p<0.005), with minimal change in the PAI/PA ratio. These results demonstrate that varicose veins are characterized by a higher than normal TIMP/MMP ratio, which may facilitate extracellular matrix accumulation in the diseased venous wall.

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Assessment of wall structure and composition of varicose veins with reference to collagen, elastin and smooth muscle content

Abstract: This suggests that varicose veins are a dynamic response to venous hypertension and are not thin walled structures as previously thought.

Cited by 150 publications

References 14 publications

Smooth Muscle Changes in Varicose Veins: An Ultrastructural Study

Smooth Muscle Changes in Varicose Veins: An Ultrastructural Study

Arterialization and anomalous vein wall remodeling in varicose veins is associated with upregulated FoxC2-Dll4 pathway

Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation

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