Abstract
The application of fluid shear stress to endothelial cells elicits the formation of nitric oxide (NO) and phosphorylation of the endothelial NO synthase (eNOS). Shear stress also elicits the enhanced tyrosine phosphorylation of endothelial proteins, especially of those situated in the vicinity of cell-cell contacts. Since a major constituent of these endothelial cell-cell contacts is the platelet endothelial cell adhesion molecule-1 (PECAM-1) we assessed the role of PECAM-1 in the activation of eNOS. In human endothelial cells, shear stress induced the tyrosine phosphorylation of PECAM-1 and enhanced the association of PECAM-1 with eNOS. Endothelial cell stimulation with shear stress elicited the phosphorylation of Akt and eNOS as well as of the AMP-activated protein kinase (AMPK). While the shear-stress-induced tyrosine phosphorylation of PECAM-1 as well as the serine phosphorylation of Akt and eNOS were abolished by the pre-treatment of cells with the tyrosine kinase inhibitor PP1 the phosphorylation of AMPK was unaffected. Down-regulation of PECAM-1 using a siRNA approach attenuated the shear-stress-induced phosphorylation of Akt and eNOS, as well as the shear-stress-induced accumulation of cyclic GMP levels while the shear-stress-induced phosphorylation of AMPK remained intact. A comparable attenuation of Akt and eNOS (but not AMPK) phosphorylation and NO production was also observed in endothelial cells generated from PECAM-1-deficient mice. These data indicate that the shear-stress-induced activation of Akt and eNOS in endothelial cells is modulated by the tyrosine phosphorylation of PECAM-1 whereas the shear-stress-induced phosphorylation of AMPK is controlled by an alternative signaling pathway.
Highlights
Endothelial cells situated at the interface between blood and the vessel wall, play a crucial role in controlling vascular tone and homeostasis, in determining the expression of pro- and anti-atherosclerotic genes
Endothelial cell stimulation with shear stress elicited the phosphorylation of Akt and endothelial NO synthase (eNOS) as well as of the AMP-activated protein kinase (AMPK)
While the shear-stress-induced tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1) as well as the serine phosphorylation of Akt and eNOS were abolished by the pre-treatment of cells with the tyrosine kinase inhibitor
Summary
Endothelial cells situated at the interface between blood and the vessel wall, play a crucial role in controlling vascular tone and homeostasis, in determining the expression of pro- and anti-atherosclerotic genes. Many of these effects are mediated by changes in the generation and release of the vasodilator nitric oxide (NO) in response to hemodynamic stimuli exerted on the luminal surface of endothelial cells by the streaming blood (wall shear stress) and the cyclic strain of the vascular wall, which results from the pulsatile changes in blood pressure (for review, see Busse and Fleming, 2003). Shear stress and cyclic stretch can activate signaling cascades within caveolae (Rizzo et al, 1999) and focal adhesion contacts (Vuori, 1998), the lateral zone of cell-cell adhesion is thought to be the major signal transduction site for fluid shear stress (Kano et al, 2000; Fujiwara et al, 2001; Davies et al, 2003)
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