Intracellular signalling involved in modulating human endothelial barrier function - PubMed (original) (raw)

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Intracellular signalling involved in modulating human endothelial barrier function

Victor W M van Hinsbergh et al. J Anat. 2002 Jun.

Abstract

The endothelium dynamically regulates the extravasation of hormones, macromolecules and other solutes. In pathological conditions, endothelial hyperpermeability can be induced by vasoactive agents, which induce tiny leakage sites between the cells, and by cytokines, in particular vascular endothelial growth factor, which increase the exchange of plasma proteins by vesicles and intracellular pores. It is generally believed that the interaction of actin and non-muscle myosin in the periphery of the endothelial cell, and the destabilization of endothelial junctions, are required for endothelial hyperpermeability induced by vasoactive agents. Transient short-term hyperpermeability induced by histamine involves Ca2+/calmodulin-dependent activation of the myosin light chain (MLC) kinase. Prolonged elevated permeability induced by thrombin in addition involves activation of the small GTPase RhoA and Rho kinase, which inhibits dephosphorylation of MLC. It also involves the action of other protein kinases. Several mechanisms can increase endothelial barrier function, depending on the tissue affected and the cause of hyperpermeability. They include blockage of specific receptors, and elevation of cyclic AMP by agents such as beta2-adrenergic agents. Depending on the vascular bed, nitric oxide and cyclic GMP can counteract or aggravate endothelial hyperpermeability. Finally, inhibitors of RhoA activation and Rho kinase represent a potentially valuable group of agents with endothelial hyperpermeability-reducing properties.

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Figures

Fig. 1

Fig. 1

Endothelial permeability is regulated by MLC phosphorylation and reorganization of the actin cytoskeleton and by tethering forces in the intercellular junctions of endothelial cells. Actin non-muscle–myosin interaction is regulated by myosin light chain (MLC) phosphorylation, which is controlled by Ca2+/calmodulin-dependent activation of MLC kinase (MLCK) and regulation of the MLC phosphatase activity. Both tight junctions (containing occludin, claudins, ZO-1, ZO-2 and ZO-3) and adherens junctions (V,E-cadherin connected via α- and β-catenins and plakoglobin connected to the actin cytoskeleton) contribute to junctional stability. (Adapted from van Hinsbergh, 1997.)

Fig. 2

Fig. 2

Histamine increases endothelial permeability and decreases the transendothelial electrical resistance (TEER). The decrease in TEER is inhibited by the Ca2+ chelator BAPTA, the calmodulin inhibitor trifluoperazine (TFP), and the MLCK inhibitor ML-7 (van Nieuw Amerongen et al. 1998). The right panel gives a schematic representation of the mechanism by which histamine increases MLC phosphorylation and actin-non-muscle–myosin interaction. An additional effect of histamine on junctional stability remains possible.

Fig. 3

Fig. 3

Schematic representation of the effects of thrombin on the endothelial actin cytoskeleton that contribute to endothelial permeability. The Ca2+/calmodulin-dependent activation of MLCK acts together with the RhoA/Rho kinase-dependent inhibition of MLC phosphatase (Ca2+ sensitization). Thrombin can also activate MAP kinase and protein kinase C (PKC), thereby influencing actin polymerization, and on protein tyrosine kinase (PTK) activity, which may affect junctional integrity.

Fig. 4

Fig. 4

Schematic picture of the effects of Ca2+/calmodulin-dependent MLCK activity and RhoA/Rho kinase on actin–non–muscle–myosin interaction in endothelial cells. It should be noted that Rho kinase may also have additional effects on the anchoring of the actin cytoskeleton to proteins in the plasma membrane.

Fig. 5

Fig. 5

Schematic representation of the activation of the RhoA. The GTP binding form of RhoA is translocated to the membrane where it is active. Guanine exchange factors (GEFs) activate RhoA, while GTPase-activating proteins (GAPs) bring RhoA back to its inactive form. The guanine dissociation factors (GDIs) dissociate active RhoA from the membrane, facilitate its inactivation, and inhibit its activation by binding to the carboxyl-terminal part of RhoA.

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