Redox signaling responses to laminar shear stress in vascular endothelial cells

Resumen

Endothelial cells (EC) in the vascular system are constantly subjected to the frictional force of shear stress (SS) due to the pulsatile nature of blood flow. Laminar shear stress (LSS) is a protective hemodynamic regulator of endothelial function, and limits the development of different inflammatory diseases related to increased cardiovascular risk. Although high levels of ROS have been described to be toxic, substantial evidence suggests that a transient production of hydrogen peroxide (H2O2) behaves as an intracellular messenger. Our studies explored the mechanisms whereby LSS-promoted ROS generation activates key endothelial signaling pathways. We found that LSS rapidly promotes a transient production of superoxide radical anion (O2-.) and H2O2 which mediate the sequential activation of p38 MAPK, an increase in the activity of eNOS and the subsequent nitric oxide production. LSS is able to regulate the expression of antioxidant defence systems; however the early response to SS in the vascular endothelium is still unclear. We focused our attention on peroxiredoxins (PRX), which are highly sensitive enzymatic sensors of H2O2 and demonstrated that PRX3 (located in the mitochondria) is potentially regulated by flow. Our data suggested that mitochondriae behave as mechanosensor organelles in EC since LSS is able to induce mitochondrial fission mediated by Drp1, which correlates with an increase in mitochondrial membrane potential and a decrease in mitochondrial respiration. It is well known that SS induces platelet activation and the release of purine nucleotides such as ADP which interacts with endothelial receptors. Our studies have identified p38 MAPK as an upstream kinase critically involved in ADP-mediated eNOS activation, demonstrating a key role for PTEN inactivation by ADP in the sequential activation of p38 MAPK and eNOS. Our data support a model in which ADP promotes the transient inactivation of PTEN, leading to an increase in PIP3 levels, which then triggers the activation of PI3K/Akt, Rac1 and p38 MAPK, and enhanced eNOS activity. This work adds new insights into the response to fluid flow providing data for undescribed pathways on the regulation of NO. signaling and mitochondrial function in the vascular endothelium.