Endothelial permeability for macromolecules. Mechanistic aspects of pathophysiological modulation.

Abstract

The endothelium separates blood from tissue and actively regulates the exchange between these compartments. Throughout the body, this one-cell-thick lining of blood vessels extends over several thousand square meters. It harbors many receptors and functions that actively regulate the extravasation of nutrients, solutes, hormones, macromolecules, and leukocytes. If the barrier function of the endothelium does not perform appropriately, leakage of macromolecules occurs, causing edema formation and exposure of the interstitium to high concentrations of plasma constituents. In severe cases of vascular leakage, platelets will adhere to the exposed subendothelium and red blood cells may even accumulate in the interstitium. Vascular leakage may be desirable for recruiting plasma proteins, such as complement factors during infection, but it can become life-threatening, particularly when it occurs in the lungs or pericardium or when it causes hypovolemic shock. Furthermore, frequent or prolonged leakage may impair proper functioning of the affected tissue. In recent years, considerable progress has been made in understanding the molecular processes that contribute to the regulation of endothelial permeability. With the exception of the liver, adrenal, and bone marrow sinusoids, in which the endothelium has rather large pores, the endothelium constitutes a selective barrier between blood and tissue. In principle, this barrier consists of the EC monolayer and its matrix. Macromolecules can cross the endothelial barrier in three ways: (1) between the cells, through cell junctions (paracellular); (2) through the EC, via pores (diaphragms or fused vesicles); and (3) transcellularly, via shuttling vesicles and specific receptors. It is generally believed that the charge and compactness of the endothelial matrix (both glycocalyx and basal membrane) contribute additionally to the selectivity of the endothelial barrier toward molecules of different size and charge. Electron microscopic evidence strongly suggests that in tissue capillaries, hormones and macromolecules are shuttled across the endothelial barrier via vesicles, in …