doi: 10.1161/CIRCRESAHA.108.180836
© 2008 American Heart Association, Inc.
Editorials |
Choosing Sides in Polarized Endothelial Adaptation to Shear Stress
From the Department of Biomedical Engineering and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville.
Correspondence to Brian P. Helmke, PhD, Department of Biomedical Engineering, University of Virginia, P.O. Box 800759, Charlottesville, VA 22908. E-mail helmke@virginia.edu
See related article, pages 177–185
Key Words: mechanotransduction • planar cell polarity • integrin • Rac • protein kinase A (PKA)
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
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Introduction |
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The endothelium is a primary integrator of biophysical and chemical cues that guide vascular wall physiology and pathology. Normally, arterial endothelial cells appear elongated longitudinally and rest on a basement membrane of collagen type IV and laminin. In atherosclerosis, lesions form primarily near arterial bifurcations and along the inner curvature of the aorta where complex spatiotemporal profiles of hemodynamic forces exist and where endothelial cells exhibit a nonpolarized structure and upregulate expression of a provisional matrix enriched in fibronectin and fibrinogen. The regional heterogeneity in endothelial phenotype and matrix expression suggests that lesion progression requires transduction of mechanical cues associated with hemodynamic wall shear stress and artery wall stretch into biochemical signals for inflammation. Integrins have been proposed as candidate mechanotransducers capable of differentiating both physical cues and matrix composition, but an integrin-mediated mechanism that confers directionality in response to shear stress has remained elusive. In this issue of Circulation Research, Goldfinger et al1 report that shear stress activates protein kinase A (PKA) to phosphorylate
4 integrin locally at the downstream edge of endothelial cells, and phosphorylated 4 releases inhibition of the GTPase Rac1 to direct polarized reorganization of the cytoskeleton. The proposed mechanism is important not only because it improves understanding of intracellular spatial organization in mechanotransduction mechanisms but also because it suggests new avenues for engineering a healthy endothelium after bypass grafting or vascular stent procedures.
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Spatial Organization During Endothelial Mechanotransduction |
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Endothelial cells associated with an atheroprotective phenotype exhibit planar polarity characteristics that include elongated shape, actin stress fibers oriented parallel to
Related Article:
4 Integrin Phosphorylation Directs Shear Stress–Induced Endothelial Cell Alignment
Circ. Res. 2008 103: 177-185.