Pathogenesis of primary varicose veins

Lim, Chung Sim; Davies, Alun H.

doi:10.1002/bjs.6798

Cited by 227 publications

(246 citation statements)

References 102 publications

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“…Congenital or acquired failure of the venous calf pump, for example, results in venous hypertension, leading to skin damage and chronic ulceration that may be treatment resistant. Valve incompetence (reflux) is a also major feature of varicose veins (7). Better understanding of the factors regulating venous valve development should allow the identification of those at risk for venous hypertension and enable preventive and novel therapies.…”

Section: Introductionmentioning

confidence: 99%

Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice

et al. 2011

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Chronic venous disease and venous hypertension are common consequences of valve insufficiency, yet the molecular mechanisms regulating the formation and maintenance of venous valves have not been studied. Here, we provide what we believe to be the first description of venous valve morphogenesis and identify signaling pathways required for the process. The initial stages of valve development were found to involve induction of ephrin-B2, a key marker of arterial identity, by venous endothelial cells. Intriguingly, developing and mature venous valves also expressed a repertoire of proteins, including prospero-related homeobox 1 (Prox1), Vegfr3, and integrin-α9, previously characterized as specific and critical regulators of lymphangiogenesis. Using global and venous valve-selective knockout mice, we further demonstrate the requirement of ephrin-B2 and integrin-α9 signaling for the development and maintenance of venous valves. Our findings therefore identified molecular regulators of venous valve development and maintenance and highlighted the involvement of common morphogenetic processes and signaling pathways in controlling valve formation in veins and lymphatic vessels. Unexpectedly, we found that venous valve endothelial cells closely resemble lymphatic (valve) endothelia at the molecular level, suggesting plasticity in the ability of a terminally differentiated endothelial cell to take on a different phenotypic identity.

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Section: Introductionmentioning

confidence: 99%

Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice

et al. 2011

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“…In this context, we showed that these environmental conditions activate the transcription factor activator protein 1 (AP‐1), which controls expression of genes with products that promote cellular activity and proliferation in the venous wall. Among them, monocyte chemoattractant protein 1 (MCP1) contributes to the recruitment of circulating monocytes and proliferation of vascular smooth muscle cells (SMCs),5, 6 whereas matrix metalloproteinase (MMP) 2 promotes degradation and thus structural rearrangement of the extracellular matrix in the vessel wall 7, 8. Consequently, an increase in wall stress stimulates expression of MMP2 and elevates gelatinase activity in the media of affected veins and human venous SMCs (HUVSMCs) 9, 10.…”

Section: Introductionmentioning

confidence: 99%

Varicose Remodeling of Veins Is Suppressed by 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Inhibitors

Eschrich

Meyer

Kuk

et al. 2016

JAHA

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BackgroundDespite the high prevalence of chronic venous insufficiency and varicose veins in the Western world, suitable pharmaceutical therapies for these venous diseases have not been explored to date. In this context, we recently reported that a chronic increase in venous wall stress or biomechanical stretch is sufficient to cause development of varicose veins through the activation of the transcription factor activator protein 1.Methods and ResultsWe investigated whether deleterious venous remodeling is suppressed by the pleiotropic effects of statins. In vitro, activator protein 1 activity was inhibited by two 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors, rosuvastatin and atorvastatin, in stretch‐stimulated human venous smooth muscle cells. Correspondingly, both statins inhibited venous smooth muscle cell proliferation as well as mRNA expression of the activator protein 1 target gene monocyte chemotactic protein 1 (MCP1). In isolated mouse veins exposed to an increased level of intraluminal pressure, statin treatment diminished proliferation of venous smooth muscle cells and protein abundance of MCP1 while suppressing the development of varicose veins in a corresponding animal model by almost 80%. Further analyses of human varicose vein samples from patients chronically treated with statins indicated a decrease in venous smooth muscle cell proliferation and MCP1 abundance compared with samples from untreated patients.ConclusionsOur findings imply that both atorvastatin and rosuvastatin effectively inhibit the development of varicose veins, at least partially, by interfering with wall stress–mediated activator protein 1 activity in venous smooth muscle cells. For the first time, this study reveals a potential pharmacological treatment option that may be suitable to prevent growth of varicose veins and to limit formation of recurrence after varicose vein surgery.

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“…Decreasing speed or stasis of blood flow in the saphenous trunk following varicose changes, degeneration of endothelial cells, and the reduced antithrombotic function of the varicose vein wall may all cause thrombogenicity leading to the saphenous thrombus. 19) Patients in this study frequently presented with a concurrent thrombosis. They had no associated thrombotic risks, except for one patient with protein C deficiency, and their thrombi were isolated from the saphenous thrombus, except for two cases excluded from the comparison.…”

Section: Discussionmentioning

confidence: 76%

Clinical Features and Developing Risks of Saphenous Vein Thrombophlebitis

Rikimaru¹

2016

Annals of Vascular Diseases

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Pathogenesis of primary varicose veins

Cited by 227 publications

References 102 publications

Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice

Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice

Varicose Remodeling of Veins Is Suppressed by 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Inhibitors

Clinical Features and Developing Risks of Saphenous Vein Thrombophlebitis

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