Mechanotransduction at the basis of endothelial barrier function

Abstract

Destabilization of cell-cell contacts involved in the maintenance of endothelial barrier function can lead to increased endothelial permeability. This increase in endothelial permeability results in an anarchical movement of fluid, solutes and cells outside the vasculature and into the surrounding tissues, thereby contributing to various diseases such as stroke or pulmonary edema. Thus, a better understanding of the molecular mechanisms regulating endothelial cell junction integrity is required for developing new therapies for these diseases. In this review, we describe the mechanotransduction mechanism at the basis of adherens junction strengthening at endothelial cell-cell contacts. More particularly, we report on the emerging role of α-catenin and EPLIN that act as a mechanotransmitter of myosin-IIgenerated traction forces. The interplay between α-catenin, EPLIN and the myosin-II machinery initiates the junctional recruitment of vinculin and α-actinin leading to a drastic remodeling of the actin cytoskeleton and to cortical actin ring reshaping. The pathways initiated by tyrosine phosphorylation of VE-cadherin at the basis of endothelial cell-cell junction remodeling is also reported, as it may be interrelated to α-catenin/ EPLIN-mediated mechanotransduction mechanisms. We also describe the junctional mechanosensory complex composed of PECAM-1, VE-cadherin and VEGFR2 that is able to transmit signaling pathway under the onset of shear stress. This mechanosensing mechanism, involved in the earliest events promoting atherogenesis, is required for endothelial cell alignment along flow direction.

Keywords: adherens junctions; biology of endothelial barrier; junction and cancer; junction and signaling; leukocyte-endothelial interactions.

Figure 1. Side-view of cells adhering to ECM via FA and to each other via TJ and AJ. Tangential (○) and centripetal (→) forces exerted by actomyosin

Figure 2.

Organization and cytoskeletal relationship of cadherin-catenin complex. Adapted from reference .

Figure 3. Schematic representation of the a-catenin molecule and its binding capacity Adapted from reference .

Figure 4. Force-dependent molecular mechanism at the basis of the junctional recruitment of vinculin by a-catenin. Under low tension, a-catenin exhibits a folded conformation sheltering a buried vinculin-binding site. Tension exerted by actomyosin filaments unfurls a-catenin unmasking a vinculin-binding site.^, X represents an a-catenin partner able to transmit actomyosinmediated tension. Adapted from reference .

Figure 5. Hypothetic role of the EPLIN-a-catenin transmitter in the recruitment of vinculin at interendothelial AJs. (A) In the absence of EPLIN, the tension exerted by the actomyosin machinery is not transmitted to a-catenin. a-catenin adopts a folded conformation that prevents vinculin binding. (B) The traction exerted by actomyosin machinery is blocked by blebbistatin, an inhibitor of myosin-II. Despite the presence of EPLIN, a-catenin adopts a folded conformation and vinculin is not recruited at the AJ. (C) When the traction exerted by the actomyosin machinery is transmitted through EPLIN, a-catenin unfurls unmasking a vinculin-binding site. This allows vinculin recruitment at endothelial cell–cell junctions. (D) Once recruited at AJ, vinculin adopts an open conformation unmasking potential binding sites for additional actin-binding proteins X.

Figure 6. Impact of shear stress on AJ and FA structures. At the apical surface of endothelial cells, shear stress induces the deflection of proteoglycans within the glycocalyx coating leading to deformation of plasma membrane. As endothelial cells elaborate cell–cell contacts, the a-catenin-EPLIN mechanotransmitter recruits vinculin and a-actinin at AJs. This is detrimental for FAs that contain decreasing vinculin and a-actinin. Shear stress activates the kinase Src that tyrosine phosphorylates VE-cadherin.