Targets for pharmacological intervention of endothelial hyperpermeability and barrier function

Many diseases share the common feature of vascular leakage, and endothelial barrier dysfunction is often the underlying cause. The subsequent stages of endothelial barrier dysfunction contribute to endothelial hyperpermeability. Vasoactive agents induce loss of junctional integrity, a process that involves actin-myosin interaction. Subsequently, the interaction of leukocytes amplifies leakage by the leukocyte-derived mediators. The processes mainly occur at the postcapillary venules. The whole microvascular bed, including the capillaries, becomes involved in vascular leakage by the induction of angiogenesis. Plasma leakage results from gaps between endothelial cells as well as by the induction of transcellular transport pathways. Several mechanisms can improve endothelial barrier function, depending on the tissue affected and the cause of hyperpermeability. They include blockade of specific receptors and elevation of cyclic AMP (cAMP) by agents such as beta(2)-adrenergic agents. However, current therapies based on these principles often fail. Recent research has identified several new promising targets for pharmacological therapy. Endogenous compounds were also found with barrier-improving characteristics. Important insights were obtained in the different pathways involved in barrier dysfunction. Such insights regard the regulation of endothelial contraction and endothelial junction integrity: inhibitors of RhoA activation and Rho kinase represent a potentially valuable group of agents with endothelial hyperpermeability reducing properties, and strategies to target vascular endothelial growth factor (VEGF)-mediated edema are under current investigation. In clinical practice, not only tools to improve an impaired endothelial barrier function are necessary. Sometimes, a controlled, temporal, and local increase in permeability can also be desired, for example, with the aim to enhance drug delivery. Therefore, vessel leakiness is also being exploited to enable tissue access of liposomes, viral vectors, and other therapeutic agents that do not readily cross healthy endothelium. This review discusses strategies for targeting signaling molecules in therapies for diseases involving altered endothelial permeability. (C) 2003 Elsevier Science Inc. All rights reserved.