Shear stress-induced endothelial cell migration involves integrin signaling via the fibronectin receptor subunits alpha(5) and beta(1).
Endothelial cell (EC) migration is required for angiogenesis, neovascularization, and reendothelialization. Integrins, known as alphabeta-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 alpha(5) and beta(1), whereas antibodies against alpha(v)beta(3) or alpha(2)beta(1) had no effect. Cell-surface levels of the integrin alpha(5) and beta(1) 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 alpha(5) and beta(1), which serve as central mechanotransducers in ECs. Shear stress-induced enhancement of EC migration might contribute importantly to accelerated reendothelialization of denuded arteries.
Urbich
Carmen
C
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.
Dernbach
Elisabeth
E
Reissner
Agnes
A
Vasa
Mariuca
M
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D018056:Hemorheology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017469:Receptors, Fibronectin / Q000502:physiology*; D019030:Receptors, Vitronectin / Q000502:physiology*; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation
D017469:Receptors, Fibronectin; D019030:Receptors, Vitronectin; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases