ArticleLaboratory investigation; a journal of technical methods and pathology2016
Arterialization and anomalous vein wall remodeling in varicose veins is associated with upregulated FoxC2-Dll4 pathway.
Article in Laboratory investigation; a journal of technical methods and pathology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 43 citations in OpenAlex.
- Progress of the pathogenesis in varicocele: a narrative review.The Canadian journal of urology · 2026Review
- Altered venous flow drives endothelial to mesenchymal transition in varicose veins by suppressing PIEZO1-KLF2 signaling.Cellular and molecular life sciences : CMLS · 2025Article
- Glycocalyx disruption, endothelial dysfunction and vascular remodeling as underlying mechanisms and treatment targets of chronic venous disease.International angiology : a journal of the International Union of Angiology · 2024Review
- Oscillatory shear stress modulates Notch-mediated endothelial mesenchymal plasticity in cerebral arteriovenous malformations.Cellular & molecular biology letters · 2023Article
- Molecular Determinants of Chronic Venous Disease: A Comprehensive Review.International journal of molecular sciences · 2023Review
- Contribution of the Elastic Component and Venous Wall Arterialization in Patients with Venous Reflux.Journal of personalized medicine · 2022Article
- The Notch Signaling Pathway Contributes to Angiogenesis and Tumor Immunity in Breast Cancer.Breast cancer (Dove Medical Press) · 2022Review
- Article
- Chronic venous disease patients show increased IRS-4 expression in the great saphenous vein wall.The Journal of international medical research · 2021Article
- MicroRNA‑199a‑5p regulates FOXC2 to control human vascular smooth muscle cell phenotypic switch.Molecular medicine reports · 2021Article
- Vessel Enlargement in Development and Pathophysiology.Frontiers in physiology · 2021Review
- Hemodynamics mediated epigenetic regulators in the pathogenesis of vascular diseases.Molecular and cellular biochemistry · 2021Review
- The Inhibition of Prolyl Oligopeptidase as New Target to Counteract Chronic Venous Insufficiency: Findings in a Mouse Model.Biomedicines · 2020Article
- Flow cytometric characterization of the saphenous veins endothelial cells in patients with chronic venous disease and in patients undergoing bypass surgery: an exploratory study.Heart and vessels · 2020Article
- FOXC2-AS1 regulates phenotypic transition, proliferation and migration of human great saphenous vein smooth muscle cells.Biological research · 2019Article
- Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia.Microcirculation (New York, N.Y. : 1994) · 2019Article
- Article
- Role and importance of the expression of transcription factor FOXC2 in cervical cancer.Oncology letters · 2017Article
- Serum from Varicose Patients Induces Senescence-Related Dysfunction of Vascular Endothelium Generating Local and Systemic Proinflammatory Conditions.Oxidative medicine and cellular longevity · 2016Article
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.-512C>T 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, α-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.
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