Recent insights into endothelial control of leukocyte extravasation

Abstract

In the process of leukocyte migration from the circulation across the vascular wall, the crosstalk with endothelial cells that line the blood vessels is essential. It is now firmly established that in endothelial cells important signaling events are initiated upon leukocyte adhesion that impinge on the regulation of cell-cell contact and control the efficiency of transendothelial migration. In addition, several external factors such as shear force and vascular stiffness were recently identified as important regulators of endothelial signaling and, consequently, leukocyte transmigration. Here, I review recent insights into endothelial signaling events that are linked to leukocyte migration across the vessel wall. In this field, protein phosphorylation and Rho-mediated cytoskeletal dynamics are still widely studied using increasingly sophisticated mouse models. In addition, activation of tyrosine phosphatases, changes in endothelial cell stiffness as well as different vascular beds have all been established as important factors in endothelial signaling and leukocyte transmigration. Finally, I address less-well-studied but interesting components in the endothelium that also control transendothelial migration, such as the ephrins and their Eph receptors, that provide novel insights in the complexity associated with this process.

Keywords: Mechanosignaling; Rho GTPases; Tyrosine phosphorylation; VE-cadherin.

Fig. 1

Differential phosphorylation of VE-cadherin in control of TEM and permeability. a Schematic overview of (de)phosphorylation events as described in Orsenigo et al. [102]. Here, VE-cadherin is phosphorylated constitutively on Y658 and Y685 in venules and capillaries. Permeability-inducing stimuli transiently as well as shear forces constitutively downregulate this phosphorylation. Subsequent ubiquitination by an unknown ubiquitin E3-ligase initiates the internalization of de-phosphorylated VE-cadherin. b In the model derived from data by Wessel et al., Y731 is constitutively phosphorylated in venules and capillaries and Y685 is bound t the VE-PTP phosphatase, keeping phosphorylation of Y685 low. Permeability-inducing stimuli induced dissociation of VE-PTP allowing phosphorylation of Y685. Y731 does not appear to be involved in control of permeability, In contrast, leukocyte adhesion induced de-phosphorylation of Y731 by SHP2, concomitant with increased phosphorylation of Y685. The latter even may involve a p60src-FAK pathway that was implicated in VEGF-stimulated tumor cell extravasation. These events initiate binding of the AP2 component α-adaptin, triggering internalization of Y731 dephosphorylated VE-cadherin. Note that the indicated events are supposed to take place at EC junctions

Fig. 2

Schematic representation of some ‘new players’ in leukocyte TEM. a Summary of ephrin-Eph interactions implicated in TEM. As detailed in the body text, several ephrin-Eph receptor interactions have been implicated in leukocyte TEM. These involve Eph receptors and ephrin ligands on endothelial cells, as well as on transmigration leukocytes or cancer cells. Some of these interactions result in increased permeability, and effects on ICAM-1 and VCAM-1 recruitment or expression which drives TEM and atherosclerosis. However, the underlying signaling pathways remain to be further elucidated. PC prostate cancer. b The ReticulonA/B proteins have been found to negatively regulate p60Src/Pyk2-mediated tyrosine phosphorylation of VE-cadherin, downstream from ICAM-1 clustering. ReticulonA/B proteins are largely residing in the endoplasmic reticulum, but are also found at the plasma membrane. The TRPC6 calcium channel as well as the Pannexin 1 ATP transporter have both been identified as positive regulators of leukocyte TEM. TRPC6 regulates, downstream, from clustered PECAM-1, the LBRC which mediated TEM. Pannexin 1-driven ATP export can activate leukocytes, thus stimulating TEM in the extracellular milieu. LBRC later border recycling compartment