Endothelial cell-cell adhesion and signaling

Abstract

Endothelial cells line blood vessels and provide a dynamic interface between the blood and tissues. They remodel to allow leukocytes, fluid and small molecules to enter tissues during inflammation and infections. Here we compare the signaling networks that contribute to endothelial permeability and leukocyte transendothelial migration, focusing particularly on signals mediated by small GTPases that regulate cell adhesion and the actin cytoskeleton. Rho and Rap GTPase signaling is important for both processes, but they differ in that signals are activated locally under leukocytes, whereas endothelial permeability is a wider event that affects the whole cell. Some molecules play a unique role in one of the two processes, and could therefore be targeted to selectively alter either endothelial permeability or leukocyte transendothelial migration.

Keywords: Actin cytoskeleton; Adherens junctions; Cell signaling; Endothelial cells; GTPases; Rap GTPases; Rho; Tight junctions.

Fig. 1

The main transmembrane proteins in endothelial cell-cell junctions. Endothelial cells line the blood stream and are constantly exposed to fluid shear stress (top panel). The bottom panel shows the main transmembrane proteins in endothelial cell-cell junctions (right). They are associated with tight junctions or adherens junctions as indicated, with the exception of PECAM-1, which is not associated with either type of junction. Three different claudin, JAM and nectin genes are reported to be expressed in endothelial cells (numbers/letters indicated under protein name). Intracellular proteins link transmembrane proteins to the actin cytoskeleton. There are additional junctional molecules, such as CD99 and ESAM, which are omitted for clarity.

Fig. 2

Signaling molecules that regulate vascular permeability. The main junctional proteins that regulate vascular permeability are shown on the right cell. The left cell shows examples of receptors that increase vascular permeability, and the intracellular signaling molecules that contribute to this response, focusing on those regulated by Rho and Rap GTPases. ROS, reactive oxygen species.

Fig. 3

Signaling molecules that regulate leukocyte transendothelial migration. Leukocyte attachment to and transmigration across endothelial cells is a multistep process, involving a variety of different adhesion molecules on leukocytes and endothelial cells (top panel). During transendothelial migration, endothelial adhesion molecules ICAM-1, VCAM-1 and PECAM-1 interact with leukocytes and transmit signals into the endothelial cell (bottom panel), which promote the transmigration process. The left cell shows signals involving RhoG, Rac1 and Rap1 GTPases; the right cell shows signals involving RhoA. LBRC, lateral border recycling compartment; ROS, reactive oxygen species.