A Mechanosensory Complex That Mediates the Endothelial Cell Response to Fluid Shear Stress

Nature. 2005 Sep 15;437(7057):426-31. doi: 10.1038/nature03952.

Abstract

Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis, 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 expression. 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-kappaB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cattle
  • Cell Adhesion
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Female
  • Gene Deletion
  • Mechanotransduction, Cellular / physiology*
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • NF-kappa B / metabolism
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism*
  • Rats
  • Stress, Mechanical
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Antigens, CD
  • Cadherins
  • Multiprotein Complexes
  • NF-kappa B
  • Platelet Endothelial Cell Adhesion Molecule-1
  • cadherin 5
  • Vascular Endothelial Growth Factor Receptor-2