RGD Reference Report - Arterialization and anomalous vein wall remodeling in varicose veins is associated with upregulated FoxC2-Dll4 pathway. - Rat Genome Database

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

Authors: Surendran, S  S Ramegowda, K  Suresh, A  Binil Raj, SS  Lakkappa, RK  Kamalapurkar, G  Radhakrishnan, N  C Kartha, C 
Citation: Surendran S, etal., Lab Invest. 2016 Apr;96(4):399-408. doi: 10.1038/labinvest.2015.167. Epub 2016 Jan 25.
RGD ID: 11529441
Pubmed: PMID:26808710   (View Abstract at PubMed)
DOI: DOI:10.1038/labinvest.2015.167   (Journal Full-text)

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, alpha-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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
DLL4Humanvaricose veins  IEP mRNA,protein:increased expression:vein:RGD 
Dll4Ratvaricose veins  ISODLL4 (Homo sapiens)mRNA,protein:increased expression:vein:RGD 
Dll4Mousevaricose veins  ISODLL4 (Homo sapiens)mRNA,protein:increased expression:vein:RGD 
EFNB2Humanvaricose veins  IEP mRNA,protein:increased expression:vein:RGD 
Efnb2Ratvaricose veins  ISOEFNB2 (Homo sapiens)mRNA,protein:increased expression:vein:RGD 
Efnb2Mousevaricose veins  ISOEFNB2 (Homo sapiens)mRNA,protein:increased expression:vein:RGD 
HEY2Humanvaricose veins  IEP mRNA,protein:increased expression:nucleus, vein:RGD 
Hey2Ratvaricose veins  ISOHEY2 (Homo sapiens)mRNA,protein:increased expression:nucleus, vein:RGD 
Hey2Mousevaricose veins  ISOHEY2 (Homo sapiens)mRNA,protein:increased expression:nucleus, vein:RGD 
PECAM1Humanvaricose veins  IEP mRNA,protein:decreased expression:endothelium:RGD 
Pecam1Ratvaricose veins  ISOPECAM1 (Homo sapiens)mRNA,protein:decreased expression:endothelium:RGD 
Pecam1Mousevaricose veins  ISOPECAM1 (Homo sapiens)mRNA,protein:decreased expression:endothelium:RGD 
VIMHumanvaricose veins  IEP mRNA,protein:increased expression:vein:RGD 
VimRatvaricose veins  ISOVIM (Homo sapiens)mRNA,protein:increased expression:vein:RGD 
VimMousevaricose veins  ISOVIM (Homo sapiens)mRNA,protein:increased expression:vein:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dll4  (delta like canonical Notch ligand 4)
Efnb2  (ephrin B2)
Hey2  (hes-related family bHLH transcription factor with YRPW motif 2)
Pecam1  (platelet and endothelial cell adhesion molecule 1)
Vim  (vimentin)

Genes (Mus musculus)
Dll4  (delta like canonical Notch ligand 4)
Efnb2  (ephrin B2)
Hey2  (hairy/enhancer-of-split related with YRPW motif 2)
Pecam1  (platelet/endothelial cell adhesion molecule 1)
Vim  (vimentin)

Genes (Homo sapiens)
DLL4  (delta like canonical Notch ligand 4)
EFNB2  (ephrin B2)
HEY2  (hes related family bHLH transcription factor with YRPW motif 2)
PECAM1  (platelet and endothelial cell adhesion molecule 1)
VIM  (vimentin)


Additional Information