Intracellular signalling involved in modulating human endothelial barrier function

Abstract

The endothelium actively regulates the extravasation of solutes, hormones and macromolecules. In pathological conditions endothelial hyperpermeability can be induced by vasoactive agents that induce tiny leakage sites between the cells, and by cytokines, in particular vascular endothelial growth factor, that increase exchange of plasma proteins by vesicles and intracellular pores. It is generally believed that the interaction of actin and nonmuscle myosin in the periphery of the endothelial cell is required for endothelial hyperpermeability induced by vasoactive agents. Histamine causes a transient increase in endothelial permeability which normalises within seversal minutes. By H1‐receptor activation it raises the cytoplasmic Ca2+ concentration and stimulates the Ca2+/calmodulin dependent activation of the myosin light chain (MLC) kinase. The phophorylated MLC promotes actin‐non–muscle–myosin interaction in the endothelial cell. Thrombin induces a prolonged hyperpermeability in human endothelial monolayers. In addition to the Ca2± dependent activation of MLC kinase, a sensitisation of the cell occurs by activation of RhoA and Rho kinase. Furthermore, protein tyrosine kinase activity contributes to the thrombin‐induced hyperpermeability.In most types of endothelia the barrier function of endothelial cells is improved both in vivo and in vitro by agents that increase the cellular cyclic AMP concentration. Catecholamines contribute to the enforcement of the endothelial barrier function by activation of (2‐adrenergic receptors and increasing the endothelial cyclic AMP content. Nitric oxide and cyclic GMP can also counteract thrombin‐induced endothelial hyperpermeability in specific types of vessels while in other types they contribute to endothelial hyperpermeability. In human aorta endothelial cells NO induced by vasoactive agents increases the generation of cGMP, which activates cGMP‐dependent protein kinase‐I. This activity counteracts the effect on endothelial permeability by reducing the elevation of Ca2+ in the cell. Furthermore inhibitors of RhoA formation and Rho kinase represent a potentially valuable additional group of agents with endothelial hyperpermeability reducing properties. They not only reduce thrombin‐induced endothelial permeability in vitro but also reduced the interaction of leukocytes with the endothelial cells and accompanying vascular leakage in vivo.