Invited Symposium: Signal Transduction in Endothelium: Mechano-Sensing, Ion Channels and Intracellular Calcium
Kettlun, C.S. (Lab. Cell Biology, Univ. Wisc. Med. School, USA)
Wigboldus, J. (Lab. Cell Biology, Univ. Wisc. Med. School, USA)
Waters, C.R. (Lab. Cell Biology, Univ. Wisc. Med. School, USA)
Sukovich, D.A. (Cardiovascular Research, Berlex Biosciences, Richmond, CA, USA)
Rubanyi, G.M. (Cardiovascular Research, Berlex Biosciences, Richmond, CA, USA)
The focal establishment of atherosclerotic lesions in distinct segments of arterial vessels exposed to perturbed (low shear, non-laminar, pulsatile), blood flow (PF) is preceded by the upregulation of endothelial cell (EC) adhesion molecules, such as Vascular Cell Adhesion Molecule-1 (VCAM-1) in these sites of 'atherosclerotic predilection'. To test the hypothesis that low-shear PF conditions activate the expression of adhesion molecules on cultured EC's, we exposed human aortic EC in specially designed flow/cell culture chambers to PF (0.01 - 1.5 dynes/cm2, 100 ml/min) and measured the expression of VCAM-1 using a whole cell ELISA. In contrast to the well-studied downregulation of VCAM-1 in EC exposed to laminar shear stress, exposure for 5 hours to PF resulted in a > 7 fold upregulation of VCAM-1, which was abrogated by antioxidants (PDTC, NAC). PF activated distinct cellular signaling pathways, such as the MAPK cascade (erk-1/2), as well as integrin-mediated signaling (FAK and paxillin). Using electrophoretic mobility shift assays, we failed to detect PF-mediated enhanced nuclear translocation of the redox-sensitive transcription factors NF-kappaB and AP-1. This result is surprising, since both these transcription factors are activated by laminar flow. By contrast, exposure to PF resulted in the upregulation of two other transcription factors, SP-1 and EGR-1. These results suggest that exposure of cultured endothelial cells to PF can mimic early manifestations of atherosclerotic lesions, such as the upregulation of VCAM-1.
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|Lelkes, P.I.; Kettlun, C.S.; Wigboldus, J.; Waters, C.R.; Sukovich, D.A.; Rubanyi, G.M.; (1998). Signaling Mechanisms Involved in Endothelial Cell Activation by Perturbed Flow. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/nilius/lelkes0243/index.html|
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