Biomolecular Mechanisms in Varicose Veins Development

doi:10.1016/j.avsg.2014.10.009

Annals of Vascular Surgery

Volume 29, Issue 2, February 2015, Pages 377-384

https://doi.org/10.1016/j.avsg.2014.10.009 Get rights and content

Varicose veins (VVs) can be described as tortuous and dilated palpable veins, which are more than 3 mm in diameter. They are one of the clinical presentations of chronic venous disorders, which are a significant cause of morbidity. The prevalence of VVs has been estimated at 25–33% in women and 10–20% in men and is still increasing at an alarming rate. Family history, older age, female, pregnancy, obesity, standing occupations, and a history of deep venous thrombosis are the predominant risk factors. A great amount of factors are implicated in the pathogenesis of VVs, including changes in hydrostatic pressure, valvular incompetence, deep venous obstruction, ineffective function of calf muscle pump, biochemical and structural alterations of the vessel wall, extracellular matrix abnormalities, impaired balance between growth factors or cytokines, genetic alterations, and several other mechanisms. Nevertheless, the issue of pathogenesis in VVs is still not completely known, even if a great progress has been made in understanding their molecular basis. This kind of studies appears promising and should be encouraged, and perhaps the new insight in this matter may result in targeted therapy or possibly prevention.

Introduction

Varicose veins (VVs) can be described as tortuous and dilated palpable veins, which are more than 3 mm in diameter. They are one of the clinical presentations of chronic venous disorder (CVD). This disease also includes telangiectases, defined as dilated intradermal venules less than 1 mm in diameter, reticular veins that are dilated and nonpalpable subdermal veins from 1 to 3 mm, pigmentation, lipodermatosclerosis, edema, and venous ulcerations. These skin changes with concomitant venous hypertension and truncal varicosities are the features of chronic venous insufficiency (CVI).¹

The Clinical-Etiology-Anatomy-Pathophysiology classification, proposed by the committee of the American Venous Forum in 1994, divides CVDs into classes, including clinical class, etiology, anatomic distribution of reflux and obstruction in the superficial, deep, and perforating vein, and pathophysiology, leading to this disease. Class 0 represents lack of venous disease. Class 1 describes limbs with telangiectases or reticular veins, whereas VVs are tantamount to class 2. Class 3 means lower extremity with edema, class 4 with skin changes without ulceration, class 5 with healed ulcers, and class 6 with active ulcers. When CVD is triggered by an identifiable event, such as an episode of deep vein thrombosis, it is classified as secondary CVD. Primary venous disorder is not preceded by a known pathology. When considering the criterion of underlying pathophysiology, we can divide chronic venous disease into cases caused by reflux, obstruction, reflux and obstruction, or lacking familiar venous pathophysiology.²

CVDs are a significant cause of morbidity and a vital health care problem, constantly generating increasing health care costs. In the United States, the prevalence of CVI has been estimated at 10–35% and the population-based costs at the level of 1 billion dollars a year.³ The Edinburg Vein Study, conducted on 1566 men and women aged 18–64 years, demonstrated that 13-year incidence of reflux was 12.7%.⁴ A great progress has been made in understanding the pathogenesis of VVs; however, it is still not completely known.

Section snippets

Epidemiology and Risk Factors

The prevalence of VVs has been estimated at 25–33% in women and 10–20% in men,5, 6, 7 whereas the prevalence of skin changes at 3–13%, and the prevalence of venous ulcerations at 1–2.7%. The Framingham study established that annual incidence of VVs was 2.6% in females and 1.9% in males, and the prevalence has been assessed at 1% in males and 10% in females aged younger than 30 years, whereas the prevalence was 57% in men and 77% in women aged older than 70 years.⁸ Family history, older age,

Venous Hypertension

Communicating and perforating veins connect the superficial to the deep venous system. The blood flows from the superficial to the deep system. Valves and calf muscle pump prevent the backflow. Deep venous obstruction, congenital absence of valves, and ineffective function of calf muscle pump are responsible for venous hypertension. The incompetence of the major communications between the superficial and deep veins of the limb is critical to the development of this condition. Chronic

Vessel Wall Alterations

Vein wall is composed of 3 layers: tunica adventitia, tunica media, and tunica intima. Muscle fibers, collagen, fibroblasts, smooth muscle cells (SMCs), and vasa vasorum form the tunica adventitia. Tunica media is composed of collagen, elastin, proteoglycans, and 3 layers of SMCs, including an inner longitudinal layer, which is thicker at valve sites, circular layer, and an outer longitudinal layer. Tunica intima consists of endothelial cells and is supported by an internal elastic lamina.

Matrix Metalloproteinases and their Inhibitors

MMPs and tissue inhibitors of MMPs (TIMPs) play a significant role in matrix deposition and tissue remodeling. MMPs, predominantly localized in the tunica adventitia, are zinc-dependent endopeptidases responsible for degrading ECM proteins. They are also involved in the cleavage of cell surface receptors, cell proliferation, migration, differentiation, angiogenesis, and apoptosis. Studies demonstrated weaker expression of MMPs, MMP-1, MMP-2, and MMP-9, in VVs compared with normal veins and

Inflammation in Varicose Veins Development

Several studies revealed a significant increase of both mast cells and monocyte or macrophage in the VV as compared with the healthy vein tissues.46, 47, 48 The monocyte and/or macrophage infiltration of inflammatory cells was distributed predominantly in the proximal wall both on and under the endothelium and in the valve sinus, which can result in valve insufficiency.47, 48 However, Sayer and Smith⁴⁶ demonstrated that there was no significant variation in the distribution of any of the

Growth Factors

Transforming growth factor beta (TGF-β) is a protein, which plays an important role in proliferation, differentiation, adhesion, and migration of cells. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are the main regulators of angiogenesis and vasculogenesis, whereas basic fibroblast growth factor (bFGF) has been implicated in mitogenic and angiogenic activities. Dermal biopsies of patients with class 4, 5, and 6 of chronic venous disease showed

Genetic Predispositions

The importance of genetic factors in venous pathologies has been confirmed in many studies. A positive family history is a known risk factor for vasovagal syncope.⁵⁵ More than 60% of the variation in susceptibility to venous thrombosis is associated with genetic alterations.⁵⁶ The study conducted by Brinsuk et al. on venous function in 46 twin pairs revealed that unadjusted heritability was 0.6 (P < 0.05) for venous capacity and 0.9 (P < 0.05) for venous compliance. The heritability estimate

Other Factors Associated with Varicose Veins

Thrombomodulin (TM) is an endothelial cell surface glycoprotein receptor, which converts thrombin from a procoagulant to an anticoagulant enzyme. The TM gene is located on chromosome 20 and includes no introns. TM is expressed on endothelial cells, leucocytes, and SMCs. Overexpression of wild-type TM reduced cell proliferation in vitro and tumor growth in vivo⁷⁵ and induced atherosclerosis due to increased amount of vascular SMCs.⁷⁶ The −1208/−1209 TT deletion contributes to the pathogenesis of

Summary

CVDs are a significant cause of morbidity with constantly increasing prevalence in Western countries. VVs are responsible for lowering quality of life because of many frequent symptoms, including heaviness of the legs, swelling, pain during standing, or ulcerations, therefore, VVs are an important health care problem.

A great amount of factors are implicated in the pathogenesis of VVs, such as changes in hydrostatic pressure, valvular incompetence, deep venous obstruction, ineffective function

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To evaluate the development of jejunal varix, the preoperative and postoperative follow-up CT images were compared. Jejunal varix was defined as tortuous dilation of veins >3 mm in diameter at the site of the choledochojejunostomy.11,12 The date on which the varix was first observed on CT images was taken as the date of jejunal varix formation.
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NLRC5 modulates phenotypic transition and inflammation of human venous smooth muscle cells by activating Wnt/β-catenin pathway via TLR4 in varicose veins
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In varicose veins, abnormal phenotypic transition and inflammatory response is commonly found in venous smooth muscle cells (VSMCs). We aimed to explore the potential role and mechanism of NLRC5 exerted on VSMCs phenotypic transition and inflammation. NLRC5 expression was detected in varicose veins and platelet-derived growth factor (PDGF)-induced VSMCs by RT-qPCR and Western bolt assays. A loss-of-function assay was performed to evaluate the effects of NLRC5 knockdown on VSMC proliferation, migration, and phenotypic transition. ELISA was used to detect the contents of pro-inflammatory cytokines in the supernatant. The modulation of NLRC5 on TLR4 expression and Wnt/β-catenin signaling was also evaluated. We found that the expressions of NLRC5 in varicose veins and PDGF-induced VSMCs were upregulated. NLRC5 knockdown inhibited VSMC proliferation and migration. Extracellular matrix transformation was blocked by downregulating NLRC5 with increasing SM-22α expression and MMP-1/TIMP-1 ratio, as well as decreasing OPN and collagen I expressions. Besides, NLRC5 silencing reduced the contents of inflammatory cytokines. Furthermore, we found that NLRC5 regulated TLR4 expression, as well as subsequently activation of Wnt/β-catenin pathway and nuclear translocation of β-catenin, which was involved in NLRC5-mediated phenotypic transition and inflammatory in VSMCs. In conclusion, silencing NLRC5 depressed VSMCs' phenotypic transition and inflammation by modulating Wnt/β-catenin pathway via TLR4. This may provide a theoretical basis for treatment of varicose veins.
Association of varicose veins with rare protein-truncating variants in PIEZO1 identified by exome sequencing of a large clinical population
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The present study sought to determine whether protein-truncating variants (PTVs) in PIEZO1 and CASZ1 genes, previously shown to be associated with varicose veins, were associated with an altered risk of varicose veins.
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General ReviewBiomolecular Mechanisms in Varicose Veins Development

Introduction

Section snippets

Epidemiology and Risk Factors

Venous Hypertension

Vessel Wall Alterations

Matrix Metalloproteinases and their Inhibitors

Inflammation in Varicose Veins Development

Growth Factors

Genetic Predispositions

Other Factors Associated with Varicose Veins

Summary

J Vasc Surg

J Vasc Surg

J Clin Epidemiol

Ann Epidemiol

J Vasc Surg

Am J Prev Med

J Vasc Surg

J Vasc Surg

J Vase Surg

Mol Med Today

Eur J Vasc Endovasc Surg

J Vasc Surg

J Vasc Surg

Eur J Vasc Endovasc Surg

J Vasc Surg

J Surg Res

J Vasc Surg

J Vasc Surg

J Surg Res

Ann Vasc Surg

J Invest Dermatol

Eur J Vasc Endovasc Surg

J Vasc Surg

Surgery

Ann Vasc Surg

Eur J Vasc Endovasc Surg

Lancet

Am J Hum Genet

J Surg Res

Gene Expr Patterns

Am J Hum Genet

Eur J Radiol

Blood

Cancer Genet Cytogenet

J Vasc Surg

J Vasc Surg

Eur J Vasc Endovasc Surg

Eur J Vasc Endovasc Surg

State-of-the-art treatment of venous disease

Clin Infect Dis

Epidemiology of varicose veins. A review

Int Angiol

Prevalence and risk factors of chronic venous insufficiency

Angiology

Importance of the familial factor in varicose disease: clinical study of 134 families

J Dermatol Surg Oncol

General Review
Biomolecular Mechanisms in Varicose Veins Development