Endothelial E-type prostanoid 4 receptors promote barrier function and inhibit neutrophil trafficking.
BACKGROUND
Increased vascular permeability is a fundamental characteristic of inflammation. Substances that are released during inflammation, such as prostaglandin (PG) E(2), can counteract vascular leakage, thereby hampering tissue damage.


OBJECTIVE
In this study we investigated the role of PGE(2) and its receptors in the barrier function of human pulmonary microvascular endothelial cells and in neutrophil trafficking.


METHODS
Endothelial barrier function was determined based on electrical impedance measurements. Neutrophil recruitment was assessed based on adhesion and transendothelial migration. Morphologic alterations are shown by using immunofluorescence microscopy.


RESULTS
We observed that activation of E-type prostanoid (EP) 4 receptor by PGE(2) or an EP4-selective agonist (ONO AE1-329) enhanced the barrier function of human microvascular lung endothelial cells. EP4 receptor activation prompted similar responses in pulmonary artery and coronary artery endothelial cells. These effects were reversed by an EP4 antagonist (ONO AE3-208), as well as by blocking actin polymerization with cytochalasin B. The EP4 receptor-induced increase in barrier function was independent of the classical cyclic AMP/protein kinase A signaling machinery, endothelial nitric oxide synthase, and Rac1. Most importantly, EP4 receptor stimulation showed potent anti-inflammatory activities by (1) facilitating wound healing of pulmonary microvascular endothelial monolayers, (2) preventing junctional and cytoskeletal reorganization of activated endothelial cells, and (3) impairing neutrophil adhesion to endothelial cells and transendothelial migration. The latter effects could be partially attributed to reduced E-selectin expression after EP4 receptor stimulation.


CONCLUSIONS
These data indicate that EP4 agonists as anti-inflammatory agents represent a potential therapy for diseases with increased vascular permeability and neutrophil extravasation.
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
Viktoria
V
Konya
Andreas
A
Üllen
Nora
N
Kampitsch
Anna
A
Theiler
Sonia
S
Philipose
Gerald P
GP
Parzmair
Gunther
G
Marsche
Bernhard A
BA
Peskar
Rufina
R
Schuligoi
Wolfgang
W
Sattler
Akos
A
Heinemann
D000199:Actins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008738:Methyl Ethers / Q000494:pharmacology; D055806:Microvessels / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D000199:Actins; D008738:Methyl Ethers; D009281:Naphthalenes; C461399:ONO-AE1-329; D010654:Phenylbutyrates; C107953:RAC1 protein, human; D058309:Receptors, Prostaglandin E, EP4 Subtype; D003571:Cytochalasin B; D000242:Cyclic AMP; D052250:Nitric Oxide Synthase Type III; D017868:Cyclic AMP-Dependent Protein Kinases; D020830:rac1 GTP-Binding Protein; D015232:Dinoprostone