Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis1, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression2,3,4. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-κB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.
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This work was funded by the NIH. E.T. is an AHA Western States Fellow. H.D. is supported by the Department of Defense. We thank M. Ginsberg, D. Salomon, J. Quigley and R. Klemke for their help. We also thank N. Resnick for providing the PDGF-A/SSRE construct, E. Schaefer for providing the phospho-specific VEGFR2 antibodies and J. Downward for the GFP–AKT PH construct. We thank P. J. Newman, S. Chien and the Developmental Studies Hybridoma Bank for providing additional reagents. Discussions with A. W. Orr and J. S. Reader were also appreciated.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Activation of integrin αvβ3, PI 3-kinase and Src by shear stress. (PDF 168 kb)
Recruitment of actin by beads. (PDF 164 kb)
WOW-1 localises near cell-cell junctions. (PDF 70 kb)
Role of VEGFR2 in shear stress signalling. (PDF 98 kb)
Transfection of Cos7 cells (PDF 158 kb)
Integrin activation requires β-catenin. (PDF 8 kb)
Full descriptions to accompany the above Supplementary Figures. (DOC 24 kb)
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Tzima, E., Irani-Tehrani, M., Kiosses, W. et al. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437, 426–431 (2005). https://doi.org/10.1038/nature03952
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