Shear stress and the endothelial transport barrier

Abstract

The shear stress of flowing blood on the surfaces of endothelial cells that provide the barrier to transport of solutes and water between blood and the underlying tissue modulates the permeability to solutes and the hydraulic conductivity. This review begins with a discussion of transport pathways across the endothelium and then considers the experimental evidence from both in vivo and in vitro studies that shows an influence of shear stress on endothelial transport properties after both acute (minutes to hours) and chronic (hours to days) changes in shear stress. Next, the effects of shear stress on individual transport pathways (tight junctions, adherens junctions, vesicles and leaky junctions) are described, and this information is integrated with the transport experiments to suggest mechanisms controlling both acute and chronic responses of transport properties to shear stress. The review ends with a summary of future research challenges.

Figure 1

Transport pathways across the endothelium. The major transport pathways are: the tight junctions, breaks in the tight junctions, vesicles, and leaky junctions. The surface glycocalyx covers the entrance to all but the leaky junctions (figure courtesy of Limary Cancel).

Figure 2

A cartoon representation of proteoglycans and glycoproteins on the surface of endothelial cells. Caveolin-1 associates with regions high in cholesterol and sphingolipids in the membrane (darker circles, left), and forms cave-like structures, caveolae (right). Glypicans, along with their heparan sulfate chains (blue dotted lines) localize in these regions. Transmembrane syndecans are shown to cluster in the outer edge of caveolae. Besides heparan sulfate, syndecans also contain chondroitin sulfate, lower down the core protein (green dotted lines). A glycoprotein with its short oligosaccharide branched chains and their associated SA ‘caps’ are displayed in the middle part of the figure (green). Hyaluronic acid or hyaluronan is a very long glycosaminoglycans (orange dotted line), which weaves into the glycocalyx and binds with CD44. Transmembrane CD44 can have chondroitin sulfate, heparan sulfate and oligosaccharides attached to it, and localizes in caveolae. Plasma proteins (grey), along with cations and cationic amino acids (red circles) are known to associate with glycosaminoglycans. (A) The cytoplasmic domains of syndecans link it to cytoskeletal elements (red line). (B) Oligomerization of syndecans helps them make direct associations with intracellular signalling effectors. (C) A series of molecules involved with endothelial nitric oxide synthase signalling localize in caveolae. Adapted from Tarbell and Pahakis.

Figure 3

Effect of the nitric oxide synthase inhibitor NG-monomethyl-l-arginine on bovine aortic endothelial cell monolayer L_p. *P < 0.05 for NG-monomethyl-l-arginine compared with control (no inhibitor). Data are presented as mean ± SEM (adapted from Chang et al.).

Figure 4

J_v (normalized) as function of time for experiments with step change from 10 to 20 cm H₂O at 60 min without drug (open circle; n = 12) and with 100 µM NG-monomethyl-l-arginine (closed squares; n = 7). P < 0.05 for t > 210 min (adapted from Tarbell et al.).

Figure 5

Effect of steady shear stress on bovine aortic endothelial cell nitric oxide production after heparinase treatment. Nitric oxide production induced by 20 dyn/cm² steady shear stress (squares) was significantly inhibited for monolayers that were pre-treated with heparinase III. Data are represented as mean ± SE (adapted from Florian et al.).

Figure 6

Effect of heparinase treatment on bovine aortic endothelial cell L_p driven by a 10 cm H₂O pressure differential imposed at time zero. A shear stress of 20 dyn/cm² was imposed at 60 min. The shear stress response of L_p was completely inhibited when the cell monolayer was pre-treated with heparinase III (adapted from Lopez et al.).