Physiology and pathophysiology of the vascular wall / [Physiologie et pathophysiologie de la paroi vasculaire] Mechanisms of increased endothelial permeability

Abstract

The increase in endothelial permeability in response to inflammatory mediators such as thrombin and histamine is accompanied by reversible cell rounding and interendothelial gap formation, suggesting that the predominant transport pathway is a diffusive one (i.e., via cellular junctions (paracellular transport)). However, vesicle-mediated transport (i.e., via albumin-binding protein gp60) may also contribute significantly to the overall increase in permeability. 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. 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, and can thus lead to impairment of the endothelial barrier integrity. One critical signal may be based on protein kinase C isoenzyme 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. Another important event is the activation of myosin light chain kinase (MLCK), which causes an actin-myosin-based contraction that may lead to centripetal retraction of endothelial cells. Current research is being conducted at identification of protein substrates of protein kinase C isoenzymes, the specific role of their phosphorylation in barrier function, and determination of the precise role of MLCK in modulation of endothelial barrier function. Since mechanisms by which the increased permeability is returned to normal may be regulated at multiple levels (e.g., receptor desensitization, protein kinase C mediated negative feedback pathways, activation of protein phosphatases), it is also important to determine these cellular "off-switch" mechanisms.

Adenosine Receptor Signaling Modulates Permeability of the Blood–Brain Barrier

“…Additionally, evidence suggests that adenosine affects actin through Rho GTPase (Sohail et al, 2009). Importantly, inflammation caused by canonical damage signals like TNF-α and thrombin increases BBB permeability by altering tight junctions through cytoskeletal reorganization (Lum and Malik, 1996; Wojciak-Stothard et al, 1998). We propose that signaling events initiated by activation of A 1 and A 2A ARs on BECs induce similar cytoskeletal remodeling which, by changing cell shape and/or size, increases the space between endothelial cells and allows greater molecular diffusion.…”

Differential involvement of ezrin/radixin/moesin proteins in sphingosine 1-phosphate-induced human pulmonary endothelial cell barrier enhancement

“…Previous studies have proposed a working model of EC barrier regulation in which the vascular barrier is regulated by a balance between competing EC contractile forces, which generate centripetaltension, and adhesive cell-cell and cell-matrix tethering forces, imposed by focal adhesion and adherens junctions (AJ), which together regulate cell shape change [1, 2, 10-13]. EC barrier enhancement induced by S1P and other barrier protective factors, such as oxidized phospholipids, human growth factor (HGF), ATP or simvastatin requires actomyosin remodeling, including formation of a prominent cortical actin rim, peripheral accumulation of phosphorylated regulatory myosin light chains (MLC), and disappearance of central stress fibers, which is regulated by Rac-dependent mechanisms [2, 14-17].…”

Microtubules Growth Rate Alteration in Human Endothelial Cells

“…Increases in vascular permeability, common for a number of human pathological states and diseases, such as inflammation, asthma, sepsis, acute lung injury, ischemia, and diabetes, can lead to severe, and even fatal, organ dysfunction [1–6]. Previous studies, published by us and by others, have proved that normal functioning of the endothelial barrier is provided by the balance between contracting and stretching forces generated by cytoskeleton proteins [3, 5, 7–9]. Moreover, endothelial cell-cell adherens junctions (AJs), largely composed of vascular endothelial cadherin (VE-cadherin), are the basic structure of endothelial permeability regulation because of their dynamic ability to open and close [10, 11].…”