Signaling mechanisms regulating endothelial permeability.

Center of Lung and Vascular Biology, Dept. of Pharmacology (M/C 868), University of Illinois, 835 S. Wolcott Avenue, Chicago, IL 60612, USA.
Physiological Reviews (Impact Factor: 29.04). 02/2006; 86(1):279-367. DOI: 10.1152/physrev.00012.2005
Source: PubMed

ABSTRACT The microvascular endothelial cell monolayer localized at the critical interface between the blood and vessel wall has the vital functions of regulating tissue fluid balance and supplying the essential nutrients needed for the survival of the organism. The endothelial cell is an exquisite "sensor" that responds to diverse signals generated in the blood, subendothelium, and interacting cells. The endothelial cell is able to dynamically regulate its paracellular and transcellular pathways for transport of plasma proteins, solutes, and liquid. The semipermeable characteristic of the endothelium (which distinguishes it from the epithelium) is crucial for establishing the transendothelial protein gradient (the colloid osmotic gradient) required for tissue fluid homeostasis. Interendothelial junctions comprise a complex array of proteins in series with the extracellular matrix constituents and serve to limit the transport of albumin and other plasma proteins by the paracellular pathway. This pathway is highly regulated by the activation of specific extrinsic and intrinsic signaling pathways. Recent evidence has also highlighted the importance of the heretofore enigmatic transcellular pathway in mediating albumin transport via transcytosis. Caveolae, the vesicular carriers filled with receptor-bound and unbound free solutes, have been shown to shuttle between the vascular and extravascular spaces depositing their contents outside the cell. This review summarizes and analyzes the recent data from genetic, physiological, cellular, and morphological studies that have addressed the signaling mechanisms involved in the regulation of both the paracellular and transcellular transport pathways.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Reactive oxygen species (ROS) are largely considered to be pathogenic to normal endothelial function in disease states such as sepsis. We hypothesized that Angiopoietin-1 (Angpt-1), an endogenous agonist of the endothelial-specific receptor, Tie-2, promotes barrier defense by activating NADPH oxidase (NOX) signaling. Using primary human microvascular endothelial cells (HMVECs), we found that Angpt-1 stimulation induces phosphorylation of p47phox and a brief oxidative burst that is lost when chemical inhibitors of NOX activity or siRNA against the NOX component p47phox were applied. As a result, there was attenuated ROS activity, disrupted junctional contacts, enhanced actin stress fiber accumulation, and induced gap formation between confluent HMVECs. All of these changes were associated with weakened barrier function. The ability of Angpt-1 to prevent identical changes induced by inflammatory permeability mediators, thrombin and lipopolysaccharides (LPS), was abrogated by p47phox knockdown. P47phox was required for Angpt-1 to activate Rac1 and inhibit mediator-induced activation of the small GTPase RhoA. Finally, Angpt-1 gene transfer prevented vascular leakage in wildtype mice exposed to systemically administered LPS, but not in p47phox knock out (p47-/-) littermates. These results suggest an essential role for NOX signaling in Angpt-1-mediated endothelial barrier defense against mediators of systemic inflammation. More broadly, oxidants generated for signal transduction may have a barrier-promoting role in vascular endothelium.
    PLoS ONE 01/2015; 10(3):e0119577. DOI:10.1371/journal.pone.0119577 · 3.53 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: The anti-inflammatory activity of the essential oil from C. longepaniculatum was evaluated by three experimental models including the dimethyl benzene-induced ear edema in mice, the carrageenan-induced paw edema in rat and the acetic acid-induced vascular permeability in mice. The influence of the essential oil on histological changes and prostaglandin E2 (PGE2), histamine and 5-hydroxytryptamine (5-HT) production associated with carrageenan-induced rat paw edema was also investigated. The essential oil (0.5, 0.25, 0.13 ml/kg b.w.) showed significantly inhibition of inflammation along with a dose-dependent manner in the three experimental models. The anti-inflammatory activity of essential oil was occurred both in early and late phase and peaked at 4 h after carrageenan injection. The essential oil resulted in a dose dependent reduction of the paw thickness, connective tissue injury and the infiltration of inflammatory cell. The essential oil also significantly reduced the production of PGE2, histamine and 5-HT in the exudates of edema paw induced by carrageenan. Both the essential oil and indomethacin resulted relative lower percentage inhibition of histamine and 5-HT than that of PGE2 at 4 h after carrageenan injection.
    International Journal of Clinical and Experimental Medicine 01/2014; 7(12):5612-20. · 1.42 Impact Factor