Published online before print June 26, 2008, doi: 10.1161/CIRCRESAHA.108.176354
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Submitted on December 11, 2007
Revised on May 8, 2008
Accepted on June 16, 2008
Localized 
4 Integrin Phosphorylation Directs Shear Stress–Induced Endothelial Cell Alignment
Lawrence E. Goldfinger *;
From the Divisions of Rheumatology and Hematology-Oncology, Department of Medicine (L.E.G., R.S., K.K., E.T., M.H.G.), the Department of Physics (E.G., A.G.), and the Department of Bioengineering and The Whitaker Institute of Biomedical Engineering (P.N., S.C.), University of California, San Diego; the Department of Cell and Molecular Physiology (E.T.), Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill; and the Core Microscopy Facility (P.N., S.C.), Scripps Research Institute, La Jolla, Calif.
* To whom correspondence should be addressed. E-mail: goldfinger{at}temple.edu.
Vascular endothelial cells respond to laminar shear stress by aligning in the direction of flow, a process which may contribute to atheroprotection. Here we report that localized 
4 integrin phosphorylation is a mechanism for establishing the directionality of shear stress–induced alignment in microvascular endothelial cells. Within 5 minutes of exposure to a physiological level of shear stress, endothelial 4 integrins became phosphorylated on Ser988. In wounded monolayers, phosphorylation was enhanced at the downstream edges of cells relative to the source of flow. The shear-induced 4 integrin phosphorylation was blocked by inhibitors of cAMP-dependent protein kinase A (PKA), an enzyme involved in the alignment of endothelial cells under prolonged shear. Moreover, shear-induced localized activation of the small GTPase Rac1, which specifies the directionality of endothelial alignment, was similarly blocked by PKA inhibitors. Furthermore, endothelial cells bearing a nonphosphorylatable 4(S988A) mutation failed to align in response to shear stress, thus establishing 4 as a relevant PKA substrate. We thereby show that shear-induced PKA-dependent 4 integrin phosphorylation at the downstream edge of endothelial cells promotes localized Rac1 activation, which in turn directs cytoskeletal alignment in response to shear stress.
Key words: integrin • PKA • endothelial • Rac GTPase • alignment
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