David Gortler - Shear Stress and Cyclic Strain May Suppress Apoptosis in Endothelial Cells by Different Pathways

Abstract

Endothelial cells (ECs) are exposed to hemodynamic forces such as shear stress (SS) and cyclic strain (CS) in vivo. Alterations in these forces may stimulate EC growth and intimal hyperplasia, possibly by promotion of cell survival through inhibition of apoptosis. The authors examined the effect of SS and CS on inhibition of apoptosis and phosphorylation of Akt and its downstream target Bad in bovine aortic ECs in vitro. Arterial levels of laminar SS (14 dyne/cm 2 ) or CS (10%) suppressed apoptosis due to serum withdrawal in EC; this suppression due to SS or CS was completely inhibited by phosphatidylinositol 3'-kinase (PI3K) inhibition. Phosphorylation of Akt in EC exposed to SS or CS was time dependent but with maximal stimulation at 30 min (SS) or 5 min (CS); SS- or CS-induced Akt phosphorylation was inhibited in the presence of PI3K inhibition. SS-induced, but not CS-induced, phosphorylation of Bad was inhibited by PI3K inhibition. These results suggest that hemodynamic forces suppress apoptosis in ECs via phosphorylation of Akt and that SS and CS differentially activate the downstream phosphorylation of Bad, possibly by stimulating an alternate pathway. This suggests an additional mechanism by which hemodynamic forces can differentially regulate transcription in ECs, and thereby possibly maintain the viability of normal endothelium.

David Gortler, Pharm.D., FCCP, Assistant Professor of Pharmacology, Yale School of Medicine, Yale University New Haven, Connecticut, 203-772-1309