Regulation of vascular endothelial barrier function

Abstract

The increase in endothelial permeability in response to inflammatory mediators such as alpha-thrombin and histamine is accompanied by cell rounding and interendothelial gap formation, implicating that the predominant transport pathway is a diffusive one [i.e., via cellular junctions (paracellular transport)]. However, the possible contribution by vesicle-mediated transport (i.e., via albumin binding protein gp60) to the overall permeability increase needs investigation. Regulation of paracellular transport in endothelial cells is associated with modulation of actin-based systems which anchor the cell to its neighbor or extracellular matrix, thus maintaining endothelial integrity. At the cell-cell junctions, actin is linked indirectly to the plasma membrane by linking proteins (e.g., vinculin, catenins, alpha-actinin) to cadherins, which function in homophilic intercellular adhesion. Cadherins may also play a role in regulating the formation of tight junctions, which also may be associated with actin. At endothelial focal contacts, the transmembrane receptors (integrins) for matrix proteins are linked to actin via linking proteins (i.e., vinculin, talin, alpha-actinin). In response to inflammatory mediators, second messengers signal two regulatory pathways which modulate the actin-based systems, which may lead to impairment of the endothelial barrier integrity. One pathway is based on protein kinase C (PKC) isozyme-specific phosphorylation of linking proteins at the cell-cell and cell-matrix junctions. The increased phosphorylation is associated with actin reorganization, cell rounding, and increased paracellular transport. The other is the activation of myosin light-chain kinase, (MLCK), which causes an actin-myosin-based contraction that may lead to a centripetal retraction of endothelial cells. Current research is in the identification of protein substrates of PKC isozymes, the specific role of their phosphorylation in barrier function, and determining the precise role of MLCK in modulation of endothelial barrier function.

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

“…number of associated proteins that function in cell motility (37)(38)(39). It is now generally accepted that phosphorylation of the 20-kDa light chain of myosin is required to activate the myosin ATPase essential for endothelial shape changes (40).…”

RhoA Interaction with Inositol 1,4,5-Trisphosphate Receptor and Transient Receptor Potential Channel-1 Regulates Ca2+ Entry

“…3 Cells expressing control vector or TRPC1 were pretreated without or with C3 transferase after which they were loaded with fura-2AM to measure changes in cytosolic Ca 2ϩ following thrombin stimulation (Fig. 4).…”

“…The increase in [Ca 2ϩ ] i regulates responses ranging from tension development through activation of actin and myosin motors to modulation of cell-cell and cell-extracellular matrix adhesive forces (2)(3)(4). For example in endothelial cells, increase in [Ca 2ϩ ] i triggered by depletion of Ca 2ϩ stores is essential for the increase in endothelial permeability induced by thrombin (5,6).…”

“…This is followed by a more sustained response secondary to Ca 2ϩ entry through plasmalemmal channels (1,(7)(8)(9)(10)(11). The initial release of cytosolic Ca 2ϩ occurs following the heterotrimeric G protein-coupled receptor-mediated generation of inositol 1,4,5-trisphosphate (IP 3 ), which in turn binds to inositol 1,4,5-trisphosphate receptor (IP 3 R) on ER, and signals Ca 2ϩ release from ER stores. Depletion of ER Ca 2ϩ induces activation of store-operated channels (SOC), resulting in Ca 2ϩ entry and replenishment of ER stores (8,(11)(12)(13).…”

Effect of water-soluble fraction of cigarette smoke on human aortic endothelial cells – a proteomic approach

“…The significant increase on α-actinin and moesin may be relevant to endothelial permeability through their effects on cytoskeletal-plasma membrane interaction and cell surfaceextracellular matrix interaction (Bretscher et al, 2000;Louvet-Vallee, 2000;Lum et al, 1994Lum et al, , 1996. Overexpression of moesin may promote monocyte adhesions to endothelial cells through its functional interaction with adhesion molecules such as ICAM-1, VCAM-1 and Lselectin (Barreiro et al, 2002;Berryman et al, 1993;Ivetic et al, 2002).…”