Abstract
BackgroundThe shear-stress induced transcription factor KLF2 has been shown to induce an atheroprotective phenotype in endothelial cells (EC) that are exposed to prolonged laminar shear. In this study we characterized the effect of the shear stress-induced transcription factor KLF2 on regulation and composition of Weibel-Palade bodies (WPBs) using peripheral blood derived ECs.Methodology and Principal FindingsLentiviral expression of KLF2 resulted in a 4.5 fold increase in the number of WPBs per cell when compared to mock-transduced endothelial cells. Unexpectedly, the average length of WPBs was significantly reduced: in mock-transduced endothelial cells WPBs had an average length of 1.7 µm versus 1.3 µm in KLF2 expressing cells. Expression of KLF2 abolished the perinuclear clustering of WPBs observed following stimulation with cAMP-raising agonists such as epinephrine. Immunocytochemistry revealed that WPBs of KLF2 expressing ECs were positive for IL-6 and IL-8 (after their upregulation with IL-1β) but lacked angiopoietin-2 (Ang2), a regular component of WPBs. Stimulus-induced secretion of Ang2 in KLF2 expressing ECs was greatly reduced and IL-8 secretion was significantly lower.Conclusions and SignificanceThese data suggest that KLF2 expression leads to a change in size and composition of the regulated secretory compartment of endothelial cells and alters its response to physiological stimuli.
Highlights
Endothelial cells (ECs) are subjected to blood-flow generated laminar shear stress
These data suggest that KLF2 expression leads to a change in size and composition of the regulated secretory compartment of endothelial cells and alters its response to physiological stimuli
It has been reported previously that expression of KLF2 increases the secretion of von Willebrand Factor (VWF) and the average amount of Weibel-Palade bodies (WPBs)/ cell in HUVECs [3]
Summary
Endothelial cells (ECs) are subjected to blood-flow generated laminar shear stress. The laminar flow in blood vessels is pulsatile and can reach shear stress levels of 10 to 70 dyne/cm2 [1,2]. High shear stress induces an atheroprotective endothelial phenotype while absence of shear stress, as occurs near bends and at bifurcations, leads to endothelial dysfunction, characterized by a reduction in barrier function and upregulation of pro-inflammatory gene expression [2,3,4]. These sites of disturbed blood flow are more prone to atherosclerotic lesion development [2,5]. In this study we characterized the effect of the shear stress-induced transcription factor KLF2 on regulation and composition of Weibel-Palade bodies (WPBs) using peripheral blood derived ECs
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