MECHANOSENSORS PECAM-1 as Fluid Shear Stress Sensor

Mechanosensory responses of vascular endothelial cells to fluid shear stress are critical for normal control of the vascular system and are key factors in formation of atherosclerotic lesions, which are associated with branch points where blood flow is disturbed. Two papers appearing this week emphasize a central role for PECAM-1, platelet endothelial cell adhesion molecule 1, in sensing shear stress. Tzima et al. used an antibody Fab fragment that recognizes only activated α_v integrins to monitor responses of endothelial cells lacking PECAM-1 or another adhesion molecule, VE-cadherin (vascular endothelial cell cadherin). Cells lacking either molecule failed to show either the usual orientation of actin filaments with the direction of fluid flow or activation of NF-B-dependent transcription. [PECAM-1^–/– cells lacked shear stress-induced activation of the tyrosine kinase Src and consequent activation of phosphoinositide 3-kinase (PI3K) and integrins, whereas the VE-cadherin^–/– cells activated Src but not the further downstream signals.] The authors used antibody-coated magnetic beads to selectively apply force to the adhesion molecules and thus showed that PECAM-1 can directly serve as a mechanosensor. The contribution of VE-cadherin to stress sensing appeared to be independent of its function in cell adhesion. Rather, immunoprecipitation studies implicated VE-cadherin as an adaptor protein linking another critical signaling molecule, VEGFR2 (vascular endothelial growth factor receptor 2), with PI3K. Ectopic expression of PECAM-1, VE-cadherin, and VEGFR2 into COS-7 monkey cells showed that these components are sufficient to confer alignment of cells to fluid flow. PECAM-1 is also likely to contribute to early events in the development of atherosclerosis, as activation of the NF-B transcription factor and other genes thought to contribute to disease manifestation was not detected in aortas of PECAM-1^–/– mice. Fleming et al. provide evidence for a role of PECAM-1 in shear stress-induced activation of the protein kinase Akt and of endothelial nitric oxide synthase (which produces the vasodilator nitric oxide) in endothelial cells. However, they note that PECAM-1 appears not to be the only mechanosensor because, although PECAM-1-deficient cells lack the stress-induced responses noted above, activation of adenosine monophosphate-activated protein kinase (AMPK) remains intact. Thus, these authors conclude that "the endothelial response to hemodynamic stimuli most likely reflects an integrated response of multiple signaling networks at different subcellular locations."

E. Tzima, M. Irani-Tehrani, W. B. Kiosses, E. Dejana, D. A. Schultz, B. Engelhardt, G. Cao, H. DeLisser, M. A. Schwartz, A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437, 426-431 (2005). [PubMed]

I. Fleming, B. Fisslthaler, M. Dixit, R. Busse, Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J. Cell Sci. 118, 4103-4111 (2005). [Abstract] [Full Text]

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ATHEROSCLEROSIS
Signaling from the Substrate

(26 April 2005)
Sci. STKE 2005 (281), tw150. [DOI: 10.1126/stke.2812005tw150]
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