A mechanosensory complex that mediates the endothelial cell response to fluid shear stress

Abstract

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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Figure 1: Responses of PECAM-1 -/- and VE-cadherin -/- cell lines to shear stress.
Figure 2: Direct mechanotransduction and adhesion-independent role for VE-cadherin.
Figure 3: PECAM-1, VE-cadherin and VEGFR2 form a mechanosensory complex.
Figure 4: Responses in PECAM-1 -/- mice.

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Acknowledgements

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.

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Correspondence to Martin Alexander Schwartz.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure S1

Activation of integrin αvβ3, PI 3-kinase and Src by shear stress. (PDF 168 kb)

Supplementary Figure S2

Recruitment of actin by beads. (PDF 164 kb)

Supplementary Figure S3

WOW-1 localises near cell-cell junctions. (PDF 70 kb)

Supplementary Figure S4

Role of VEGFR2 in shear stress signalling. (PDF 98 kb)

Supplementary Figure S5

Transfection of Cos7 cells (PDF 158 kb)

Supplementary Figure S6

Integrin activation requires β-catenin. (PDF 8 kb)

Supplementary Figure Legends

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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