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The Assembly and Application of 'Shear Rings': A Novel Endothelial Model for Orbital, Unidirectional and Periodic Fluid Flow and Shear Stress
Published on: October 31, 2016
Localized alpha4 integrin phosphorylation directs shear stress-induced endothelial cell alignment
Lawrence E Goldfinger1, Eleni Tzima, Rebecca Stockton
1Sol Sherry Thrombosis Research Center and Department of Anatomy & Cell Biology, Temple University School of Medicine, 3400 N. Broad Street, OMS 415, Philadelphia, PA 19140, USA. goldfinger@temple.edu
Circulation Research
|June 28, 2008
Summary
Vascular endothelial cells align with blood flow via alpha4 integrin phosphorylation. This process, regulated by protein kinase A (PKA), directs cell alignment and may protect against atherosclerosis.
Area of Science:
- Cell biology
- Biophysics
- Vascular biology
Background:
- Vascular endothelial cells align with laminar shear stress, potentially contributing to atheroprotection.
- The molecular mechanisms guiding this directional alignment are not fully understood.
Purpose of the Study:
- To investigate the role of alpha4 integrin phosphorylation in shear stress-induced endothelial cell alignment.
- To elucidate the signaling pathway involving protein kinase A (PKA) and Rac1 in this process.
Main Methods:
- Exposure of microvascular endothelial cells to physiological shear stress.
- Analysis of alpha4 integrin phosphorylation at Ser(988) using Western blotting.
- Assessment of Rac1 activation and cytoskeletal organization.
- Utilizing a nonphosphorylatable alpha4 integrin mutant (S988A).
Main Results:
- Shear stress induced rapid alpha4 integrin phosphorylation at Ser(988) within 5 minutes.
- Phosphorylation was localized to the downstream edges of cells in wounded monolayers.
- Inhibition of PKA blocked both alpha4 integrin phosphorylation and Rac1 activation.
- Endothelial cells with the alpha4(S988A) mutation failed to align in response to shear stress.
Conclusions:
- Shear-induced alpha4 integrin phosphorylation at the downstream edge is a key mechanism for directional endothelial cell alignment.
- This phosphorylation event is dependent on PKA and promotes localized Rac1 activation.
- The alpha4 integrin-PKA-Rac1 pathway is crucial for directing cytoskeletal rearrangements in response to shear stress, contributing to atheroprotection.
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