Role of cadherins and plakoglobin in interendothelial adhesion under resting conditions and shear stress

Abstract

The role of cadherins and the cadherin-binding cytosolic protein plakoglobin in intercellular adhesion was studied in cultured human umbilical venous endothelial cells exposed to fluid shear stress. Extracellular Ca2+depletion (<10−7 M) caused the disappearance of both cadherins and plakoglobin from junctions, whereas the distribution of platelet endothelial cell adhesion molecule 1 (PECAM-1) remained unchanged. Cells stayed fully attached to each other for several hours in low Ca2+ but began to dissociate under flow conditions. At the time of recalcification, vascular endothelial (VE) cadherin and β-catenin became first visible at junctions, followed by plakoglobin with a delay of ∼20 min. Full fluid shear stress stability of the junctions correlated with the time course of the reappearance of plakoglobin. Inhibition of plakoglobin expression by microinjection of antisense oligonucleotides did not interfere with the junctional association of VE-cadherin, PECAM-1, and β-catenin. The plakoglobin-deficient cells remained fully attached to each other under resting conditions but began to dissociate in response to flow. Shear stress-induced junctional dissociation was also observed in cultures of plakoglobin-depleted arterial endothelial cells of the porcine pulmonary trunk. These observations show that interendothelial adhesion under hydrodynamic but not resting conditions requires the junctional location of cadherins associated with plakoglobin. β-Catenin cannot functionally compensate for the junctional loss of plakoglobin, and PECAM-1-mediated adhesion is not sufficient for monolayer integrity under flow.

VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells

“…Recent reports demonstrated changes in cellular localization of the adherens junctions components, VE-cadherin, and ␤-catenin in endothelial cells exposed to prolonged shear stress (8-24 h) and suggested a potential role for these molecules in the morphological adaptation of endothelial cells to flow (17,18). We hypothesized that the adherens junction may serve as a shearstress sensor and thus undergo fast changes in response to flow.…”

“…Recently VEGFR2 was shown to form a complex with VE-cadherin, ␤-catenin, and phosphatidylinositol 3-kinase that leads to the phosphorylation of the survival signal Akt1 (phospho-kinase B) and the induction of BclII in vascular endothelial cells (15). The adherens junction has been shown to play a role in the adaptation of vascular endothelial cells to long intervals of shear stress (17,18), but its role in mechanosensing has not been studied. The present study demonstrates that short intervals of shear stress stimulate the formation of the VEGFR2-VE-cadherin-␤-catenin complex in vascular endothelial cells, and that the complex plays a role in transducing shear stress-dependent signals into the endothelium.…”

Vascular Responses to Shear Stress: The Involvement of Mechanosensors in Endothelial Cells

“…The adherens junction has been shown to play a role in the adaptation of vascular endothelial cells to long intervals of shear stress [63,64]. In porcine aortic endothelial cells, shear stress causes partial disassembly of adherens junctions that involves complete, but temporary, loss of junctional plakoglobin and partial, transient dispersal of other catenins and VE-cadherin [63].…”

“…In porcine aortic endothelial cells, shear stress causes partial disassembly of adherens junctions that involves complete, but temporary, loss of junctional plakoglobin and partial, transient dispersal of other catenins and VE-cadherin [63]. Adherens junctions, which form a beltlike structure contiguous with the dense peripheral band in static cultures, are reassembled into adherens plaques that localize at the ends of stress fibers that insert into cell-cell junctions.…”

“…Schnittler et al showed that interendothelial adhesion under hydrodynamic but not resting conditions requires the junctional location of cadherins associated with plakoglobin. -Catenin cannot functionally compensate for the junctional loss of plakoglobin, and PECAM-1-mediated adhesion is not sufficient for monolayer integrity under flow [63]. Furthermore, the role of adherens junctions in mechanosensing was demonstrated by the formation of the VEGFR2-VE-cadherin--catenin complex in vascular endothelial cells that stimulated by short intervals of shear stress [65].…”