Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells

Abstract

PP1 the phosphorylation of AMPK was unaffected. Downregulation 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-stressinduced 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.

A model of localised Rac1 activation in endothelial cells due to fluid flow

“…Using the derived parameters (see appendix) the time-course of Src activation is comparable to previously reported (Fleming et al, 2005;Jalali et al, 1998). The whole cell response for Rac, figure 9(d), is slightly less than reported (Tzima et al, 2002).…”

“…Comparing this with the experimental observations (Jalali et al, 1998;Fleming et al, 2005) of a characteristic 2-5 fold increase in activated Src leads to a relationship between k + , k m and k − . A second relationship can be drawn by comparing the order of activation of Src in the model with experimental data.…”

“…The coupling, between extension (z e ) and the biochemical network (figure 7) is via the parameter k + (z e ), which -in the model-is the rate of Src activation. Src has been shown to be activated (either directly or indirectly) by both shear stress and applied mechanical force (Wang et al, 2005b;Jalali et al, 1998;Fleming et al, 2005). Furthermore, there is evidence that stretch activation exhibits behaviour similar to figure 8.…”

“…Note that compressive forces were assumed not to affect mechano-transducter signalling and, for simplicity, integrin clustering was coarse-grained into a smooth distribution. (Fleming et al, 2005;Jalali et al, 1998). (d) Average RacGTP concentration over the whole cell.…”

Endothelial basement membrane laminin 511 is essential for shear stress response

“…Considerable data suggest that increased force/shear stress on PECAM‐1 leads to Src kinase activation (Chiu et al , 2008) and phosphorylation and ligand independent activation of VEGFR2 and VEGFR3. Activated VEGFR2 and VEGFR3 can trigger several pathways that lead to the activation of integrins and subsequent downstream signalling, including the release of vasoactive signals and vessel dilation (Jin et al , 2003; Fleming et al , 2005). Shear detection requires cell anchorage to the underlying ECM, the nature of which appears to influence the response of the endothelium, since endothelial cells bound to fibronectin versus collagen type I lead to stronger adhesion, manifested as larger and more complex focal adhesions and stronger tension development on PECAM‐1 (Collins et al , 2014).…”