Vascular endothelial cells (ECs) are constantly exposed to hemodynamic forces, which modulates gene expression and function and hence vascular biology/pathology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with a nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. The role of epigenetic factors, including histone deacetylases (HDACs) and microRNAs (miRs) in modulating endothelial biology and pathology in responseto hemodynamic forces has recently emerged. Through investigations in cell culture, experimental animals, and clinical specimens, we have demonstrated that HDAC-3 acts as a common epigenetic factor that may concurrently modulate endothelial oxidative, inflammatory, and proliferative responses to disturbed flow. We also found that Class I HDACs are highly expressed in venous EC layers of anastomosis of arteriovenous shunt (AVS) in the rat and in patients, which may play important roles in modulating AVS thrombosis through modulation in thrombomodulin. Moreover, HDAC-3/5/7 play important roles in modulating anti-inflammatory miR-10a expression in ECs in response to disturbed flow through interactions with retinoic acid receptors. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in the pathogenesis of vascular diseases. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.
Date:
2014-08
Relation:
Journal of Vascular Research. 2014 Aug;51(Suppl. 1):7.
