Shear Stress–Induced Endothelial Cell Migration Involves Integrin Signaling Via the Fibronectin Receptor Subunits α 5 and β 1

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Abstract
Endothelial cell (EC) migration is required for angiogenesis, neovascularization, and reendothelialization. Integrins, known as αβ-heterodimeric cell-surface receptors, regulate cell migration and are essential for mechanotransduction of hemodynamic forces. Therefore, we investigated the effect of shear stress on EC migration and the contribution of the integrins and integrin-dependent signaling pathways in a scratched-wound assay. Laminar shear stress–induced EC migration was significantly reduced by integrin-receptor blocking with RGD peptides or with neutralizing antibodies against integrin subunits α5 and β1, whereas antibodies against αvβ3 or α2β1 had no effect. Cell-surface levels of the integrin α5 and β1 were specifically upregulated in migrating ECs at the wound edges. Consistent with the important role of integrins for shear stress–increased cell migration, blockade of the integrin-associated adapter protein Shc by overexpression of dominant negative construct inhibited shear stress–stimulated EC migration. Moreover, pharmacological inhibition of the integrin downstream effector signaling molecules ERK1/2 or phosphatidyl-inositol-3-kinase prevented shear stress–induced EC migration. In contrast, inhibition of the NO synthase had no effect. Taken together, our results indicate that laminar shear stress enhances EC migration via the fibronectin receptor subunits α5 and β1, which serve as central mechanotransducers in ECs. Shear stress–induced enhancement of EC migration might contribute importantly to accelerated reendothelialization of denuded arteries.