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

Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis(1), 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(2-4). 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-kappa B and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.