Maintenance of HDACs and H3K9me3 Prevents Arterial Flow-Induced Venous Endothelial Damage.

Ting-Yun Wang,Yi-Shuan Julie Li,Tzu-Chieh Huang,Shu Chien,Ming-Min Chang,Chia-Ching Wu

doi:10.3389/fcell.2021.642150

Abstract

The transition of flow microenvironments from veins to arteries in vein graft surgery induces “peel-off” of venous endothelial cells (vECs) and results in restenosis. Recently, arterial laminar shear stress (ALS) and oscillatory shear stress (OS) have been shown to affect the cell cycle and inflammation through epigenetic controls such as histone deacetylation by histone deacetylases (HDACs) and trimethylation on lysine 9 of histone 3 (H3K9me3) in arterial ECs. However, the roles of H3K9me3 and HDAC in vEC damage under ALS are not known. We hypothesized that the different responses of HDACs and H3K9me3 might cause vEC damage under the transition of venous flow to arterial flow. We found that arterial ECs showed high expression of H3K9me3 protein and were retained in the G0 phase of the cell cycle after being subjected to ALS. vECs became round under ALS with a decrease in the expression of H3K9me3, HDAC3, and HDAC5, and an increase in the expression of vascular cell adhesion molecule 1 (VCAM-1). Inhibition of HDACs activity by a specific inhibitor, phenylbutyrate, in arterial ECs caused similar ALS-induced inflammation and cell loss as observed in vECs. Activation of HDACs and H3K9me3 by ITSA-1, an HDAC activator, could prevent ALS-induced peel-off and reduced VCAM-1 expression in vECs. Moreover, shear stress modulates EC morphology by the regulation of focal adhesion kinase (FAK) expression. ITSA-1 or EGF could increase phosphorylated (p)-FAK expression in vECs under ALS. We found that perturbation of the activity of p-FAK and increase in p-FAK expression restored ALS-induced H3K9me3 expression in vECs. Hence, the abnormal mechanoresponses of H3K9me3 and HDAC in vECs after being subjected to ALS could be reversed by ITSA-1 or EGF treatment: this offers a strategy to prevent vein graft failure.

Highlights

Autologous saphenous veins are the most commonly used conduits in coronary artery bypass grafts for the treatment of coronary artery stenosis (De Vries et al, 2016; McKavanagh et al, 2017; Caliskan et al, 2020)
To investigate the role of H3K9me3 in the arterial laminar shear stress (ALS)-induced cell quiescence, first, we examined the effect of different shear stresses in modulating H3K9me3 expression in Endothelial cells (ECs)
The human umbilical vein endothelial cells (HUVECs), which are more like arterial ECs, were cultured under ST, ALS, or oscillatory shear stress (OS) conditions for 12 or 24 h; the expressions of cyclin A1, cyclin B1, and H3K9me3 were measured by Western blotting (Figure 1A)

Summary

Introduction

Autologous saphenous veins are the most commonly used conduits in coronary artery bypass grafts for the treatment of coronary artery stenosis (De Vries et al, 2016; McKavanagh et al, 2017; Caliskan et al, 2020). Failure of grafts increases the frequency of adverse cardiovascular outcomes and death. Another type of VGF can be seen in arteriovenous grafts for hemodialysis. A radiocephalic arteriovenous fistula (AVF) at the wrist is the first choice for hemodialysis access. In radiocephalic AVFs, the A-V angle between the vein and the proximal artery of juxta-anastomotic region wider than 46.5◦ leads to disturbed blood flow, which is the most common site of venous stenosis (Yang et al, 2020)

Methods

Results

Conclusion