Focal adhesion kinase regulation of mechanotransduction and its impact on endothelial cell functions

Abstract

Vascular endothelial cells lining the blood vessels form the interface between the bloodstream and the vessel wall and as such they are continuously subjected to shear and cyclic stress from the flowing blood in the lumen. Additional mechanical stimuli are also imposed on these cells in the form of substrate stiffness transmitted from the extracellular matrix components in the basement membrane, and additional mechanical loads imposed on the lung endothelium as the result of respiration or mechanical ventilation in clinical settings. Focal adhesions (FAs) are complex structures assembled at the abluminal endothelial plasma membrane which connect the extracellular filamentous meshwork to the intracellular cytoskeleton and hence constitute the ideal checkpoint capable of controlling or mediating transduction of bidirectional mechanical signals. In this review we focus on focal adhesion kinase (FAK), a component of FAs, which has been studied for a number of years with regards to its involvement in mechanotransduction. We analyzed the recent advances in the understanding of the role of FAK in the signaling cascade(s) initiated by various mechanical stimuli with particular emphasis on potential implications on endothelial cell functions.

Figure 1. Focal adhesions as ideal checkpoints controlling inside-out and inwards transduction of mechanical signals

Focal adhesion components including transmembrane integrins and intracellular Src, FAK, Paxillin, Talin, Vinculin and CAS all assemble at the cell surface to create a physical anchorage point linking the extracellular matrix to the intracellular meshwork of actin filaments.

Figure 2. Mechanical perturbations experienced by blood vessels and in particular by the inner endothelial monolayer

Figure 3. Role of Focal Adhesion Kinase (FAK) in the integration of endothelial cell response to mechanical forces

Different types of mechanical stimulations (cyclic stretch, shear forces, pressure, extra cellular matrix stiffness, hypotonic stress, etc) modulate FAK activity and interactions through phosphorylation and re-localization in the cell. By affecting focal adhesion dynamics and localization, FAK controls directional endothelial cell migration and maintains cell polarity. Signaling through ERK/p38 MAP kinase cascades to NF-κB activates or inhibits cell proliferation depending on physiological state of the cell. In parallel, FAK activation suppresses caspase-dependent apoptosis. By reconciling directional migration, proliferation/differentiation and apoptosis, FAK mediates physical force directed angiogenesis. FAK activation by disturbed flow is essential for phosphorylation of NFkB p65 subunit leading to induction of ICAM-1, endothelial activation, increased leukocyte adhesion and vascular inflammation. Depending on the type and magnitude, mechanical forces induce differential patterns of site-specific FAK phosphorylation and intracellular localization and may promote both, enhancement or weakening of vascular endothelial barrier.