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

• Published in: Laboratory investigation Vol. 96; no. 4; pp. 399 - 408
• Main Authors: Surendran, Sumi, S Ramegowda, Kalpana, Suresh, Aarcha, Binil Raj, S S, Lakkappa, Ravi Kumar B, Kamalapurkar, Giridhar, Radhakrishnan, N, C Kartha, Chandrasekharan
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.04.2016; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13/1; 13/51; 14/63; 38/90; 631/1647/2017/2003; 692/699/75/593/1920; 82; 82/51; 82/80; Actins - genetics; Actins - metabolism; Adult; Aged; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Blotting, Western; Ephrin-B2 - genetics; Ephrin-B2 - metabolism; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Middle Aged; Muscle, Smooth - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Pathology; Platelet Endothelial Cell Adhesion Molecule-1 - genetics; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; research-article; Reverse Transcriptase Polymerase Chain Reaction; Saphenous Vein - metabolism; Saphenous Vein - pathology; Saphenous Vein - physiopathology; Signal Transduction - genetics; Up-Regulation - genetics; Varicose Veins - genetics; Varicose Veins - metabolism; Vascular Remodeling - genetics; Young Adult
• DOI: 10.1038/labinvest.2015.167
• ISSN: 0023-6837

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.