Varicose veins associated with CADASIL result from a novel mutation in the
            <i>Notch3</i>
            gene

Saiki, Sachio; Sakai, Kazuhisa; Saiki, Misuzu; Kitagawa, Yoko; Umemori, T.; Murata, Kayoko; Matsui, Masaru; Hirose, Genjiro

doi:10.1212/01.wnl.0000224758.52970.19

Cited by 31 publications

(19 citation statements)

References 9 publications

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“…Also, patients with Klippel-Trenaunay syndrome often have VVs, supporting heritability of VVs (Delis et al, 2007). Other evidence for a genetic component of VVs include the following: a heterozygous mutation in the Notch3 gene identified in the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy pedigree with VVs (Saiki et al, 2006); a microarray analysis of 3063 human cDNAs from VVs showing upregulation of 82 genes, particularly those regulating ECM, cytoskeletal proteins, and myofibroblast production (Lee et al, 2005); individuals with Ehlers-Danlos syndrome type IV being prone to vascular pathology and VVs (Badauy et al, 2007); identification of single nucleotide polymorphisms in the promoter region of the MMP-9 gene among Chinese patients with VVs, with a 1562 C-to-T substitution associated with increased MMP-9 promoter activity and plasma levels (Xu et al, 2011); and the reduction of the elasticity of the lower-limb vein wall in children of VV patients (Reagan and Folse, 1971). …”

Section: Chronic Venous Diseasementioning

confidence: 96%

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

MacColl

Khalil

2015

J Pharmacol Exp Ther

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Lower-extremity veins have efficient wall structure and function and competent valves that permit upward movement of deoxygenated blood toward the heart against hydrostatic venous pressure. Matrix metalloproteinases (MMPs) play an important role in maintaining vein wall structure and function. MMPs are zinc-binding endopeptidases secreted as inactive pro-MMPs by fibroblasts, vascular smooth muscle (VSM), and leukocytes. ProMMPs are activated by various activators including other MMPs and proteinases. MMPs cause degradation of extracellular matrix (ECM) proteins such as collagen and elastin, and could have additional effects on the endothelium, as well as VSM cell migration, proliferation, Ca 21 signaling, and contraction. Increased lower-extremity hydrostatic venous pressure is thought to induce hypoxia-inducible factors and other MMP inducers/ activators such as extracellular matrix metalloproteinase inducer, prostanoids, chymase, and hormones, leading to increased MMP expression/activity, ECM degradation, VSM relaxation, and venous dilation. Leukocyte infiltration and inflammation of the vein wall cause further increases in MMPs, vein wall dilation, valve degradation, and different clinical stages of chronic venous disease (CVD), including varicose veins (VVs). VVs are characterized by ECM imbalance, incompetent valves, venous reflux, wall dilation, and tortuosity. VVs often show increased MMP levels, but may show no change or decreased levels, depending on the VV region (atrophic regions with little ECM versus hypertrophic regions with abundant ECM) and MMP form (inactive pro-MMP versus active MMP). Management of VVs includes compression stockings, venotonics, and surgical obliteration or removal. Because these approaches do not treat the causes of VVs, alternative methods are being developed. In addition to endogenous tissue inhibitors of MMPs, synthetic MMP inhibitors have been developed, and their effects in the treatment of VVs need to be examined.

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Section: Chronic Venous Diseasementioning

confidence: 96%

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

MacColl

Khalil

2015

J Pharmacol Exp Ther

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“…Chuvash polycythaemia is an autosomal recessive disorder caused by Arg200Trp mutation (C598T) of the von Hippel-Lindau gene (VHL), leading to dysfunction in oxygen tension sensing and inappropriate cellular hypoxic responses 20,21 . Other gene mutations associated with varicose vein formation include those in FOXC2, commonly found in patients with lymphoedema-distichiasis, and NOTCH3 in patients suffering from cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy 14,22,23 . FOXC2 is a gene situated on chromosome 16q24.3 that encodes a regulatory transcription factor.…”

Section: Genetic Associationsmentioning

confidence: 99%

Pathogenesis of primary varicose veins

Lim

Davies

2009

British Journal of Surgery

238

206

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Positive family history, age, sex and pregnancy are important risk factors for varicose vein formation. Areas of intimal hyperplasia and smooth muscle cell proliferation are often noted in varicose veins, although regions of atrophy are also present. The total elastin content in varicose as opposed to non-varicose veins is reduced; changes in overall collagen content are uncertain. Matrix metalloproteinases (MMPs), including MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9, and tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP-3 are upregulated in varicose veins. Activation of the endothelium stimulates the recruitment of leucocytes and the release of growth factors, leading to smooth muscle cell proliferation and migration. Dysregulated apoptosis has also been demonstrated in varicose veins. An understanding of the pathophysiology of varicose veins is important in the identification of potential therapeutic targets and treatment strategies.

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“…Alopecia (a common feature in CARASIL) or prominent lesions of the skin or other organs and systems also appear to be rare [125][126][127] . Venous insufficiency was a frequent manifestation in one oriental family 128 .…”

Section: Cadasil Andrémentioning

confidence: 99%

CADASIL: pathogenesis, clinical and radiological findings and treatment

André

2010

Arq. Neuro-Psiquiatr.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of ischemic strokes and a most important model for the study of subcortical vascular dementia. This unrelentlessly progressive disease affects many hundreds of families all over the world but is not well studied in Brazil. This manuscript reviews pathogenetic, clinical, radiological and therapeutic features of CADASIL. The causal mutations are now very well known, but the same can not be said about its intimate pathogenetic mechanisms. The variable clinical presentation should lead physicians to actively pursue the diagnosis in many settings and to more thouroughly investigate family history in first degree relatives. A rational approach to genetic testing is however needed. Treatment of CADASIL is still largely empiric. Highquality therapeutic studies involving medications and cognitive interventions are strongly needed in CADASIL. Key words: CADASIL, etiology, genetics, diagnosis, therapeutics.cADAsIL: patogênese, achados clínicos e radiológicos e tratamento resumo CADASIL é a causa genética mais freqüente de infartos cerebrais e constitui modelo importante de estudo de demências vasculares subcorticais. De natureza inexoravelmente progressiva, afeta milhares de pessoas em todo o mundo. Sua importância é pouco reconhecida entre nós, o que nos levou à presente revisão dos principais aspectos patogenéticos, clínicos, neuroradiológicos e terapêuticos da doença. As mutações causais são hoje bem conhecidas, mas os mecanismos patogenéticos íntimos ainda permanecem misteriosos. A apresentação clínica variável deve fazer com que os médicos considerem o diagnóstico em vários contextos clínicos e investiguem de forma mais extensa que o usual a história familial deparentes de primeiro grau. Além disso, uma abordagem racional é necessária para reduzir custos e aumentar a eficiência do diagnóstico genético. O tratamento atual de pacientes com CADASIL é basicamente empírico. Estudos clínicos sobre medicamentos e intervenções cognitivas de alto nível metodológico constituem uma necessidade urgente.

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Varicose veins associated with CADASIL result from a novel mutation in the Notch3 gene

Cited by 31 publications

References 9 publications

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

Pathogenesis of primary varicose veins

CADASIL: pathogenesis, clinical and radiological findings and treatment

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