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.-512C4T 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, a-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. In conjunction with the presence of genes conferring disease susceptibility, various risk factors, such as prolonged standing, an increased body mass index, and preganancy, increases the mean venous pressure, in the lower extremities. 3,4 Pfisterer et al in 2014 found in an experimental mouse model that an escalated venous filling pressure induces varicose-like venous remodeling. This process to a greater extent mimics detrimental remodeling processes observed in human varicose veins. 5 The precise molecular mechanisms underlying the pathogenesis and progression of varicose veins are unclear. We have earlier observed a significant association of FoxC2 c.-512C4T polymorphism with the presence of varicose veins in patients. FoxC2 was also upregulated at both transcript and protein levels in varicose vein tissues of patients with varicose veins. 6 In venous endothelial cells transfected with FoxC2-overexpressing mammalian vectors, the presence of putative arterial endothelial markers Delta-like ligand 4 (Dll4) and Hairy/enhancer-of-split related with YRPW motif protein 2 (Hey2) were found.

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Endocardial endothelial cells (EECs), when compared with endothelial cells of arteries and veins, possess higher resistance to apoptosis-inducing anticancer agents. The mechanism of this resistance property is unknown. We have investigated the molecular mechanism, which contributes to increased cell survival capacity in EECs. We explored whether the resistance to apoptosis is associated with the cellular expression of ATP-binding cassette transporters such as P-glycoprotein, MRP-1, and ABCG2. We used primary and immortalized porcine endocardial endothelial cells (PEECs and hTERT PEECs) and compared the results with that in porcine aortic endothelial cells (PAECs), left atrioventricular valve endothelial cells (PVECs), and human umbilical vein endothelial cell line (EA.hy926). FACS and immunoblot analysis revealed a significantly higher expression of ABCG2 in PEECs and hTERT PEECs compared to PAECs, PVECs, and EA.hy926. Using apoptosis-inducing anticancer agents such as doxorubicin and camptothecin, through chromatin condensation assay and immunoblot analysis, we demonstrated a higher resistance to apoptosis in EECs compared to PAECs, PVECs, and EA.hy926. Interestingly, resistance in EECs reversed in presence of ABCG2 specific inhibitor, fumitremorgin C. Our observations suggest that an inherently high expression of ABCG2 in EECs protects them against apoptosis in presence of anticancer agents.

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