Sphingosine-1-phosphate modulation of basal permeability and acute inflammatory responses in rat venular microvessels.
OBJECTIVE
Although several cultured endothelial cell studies indicate that sphingosine-1-phosphate (S1P), via GTPase Rac1 activation, enhances endothelial barriers, very few in situ studies have been published. We aimed to further investigate the mechanisms whereby S1P modulates both baseline and increased permeability in intact microvessels.


RESULTS
We measured attenuation by S1P of platelet-activating factor (PAF)- or bradykinin (Bk)-induced hydraulic conductivity (L(p)) increase in mesenteric microvessels of anaesthetized rats. S1P alone (1-5 µM) attenuated by 70% the acute L(p) increase due to PAF or Bk. Immunofluorescence methods in the same vessels under identical experimental conditions showed that Bk or PAF stimulated the loss of peripheral endothelial cortactin and rearrangement of VE-cadherin and occludin. Our results are the first to show in intact vessels that S1P pre-treatment inhibited rearrangement of VE-cadherin and occludin induced by PAF or Bk and preserved peripheral cortactin. S1P (1-5 µM, 30 min) did not increase baseline L(p). However, 10 µM S1P (60 min) increased L(p) two-fold.


CONCLUSIONS
Our results conform to the hypothesis that S1P inhibits acute permeability increase in association with enhanced stabilization of peripheral endothelial adhesion proteins. These results support the idea that S1P can be useful to attenuate inflammation by enhancing endothelial adhesion through activation of Rac-dependent pathways.
Adamson
Roger H
RH
Department of Physiology and Membrane Biology, School of Medicine, University of California, 1 Shields Avenue, Davis, CA 95616, USA. rhadamson@ucdavis.edu
Sarai
Rupinder K
RK
Altangerel
Ariungerel
A
Thirkill
Twanda L
TL
Clark
Joyce F
JF
Curry
Fitz-Roy E
FR
D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001920:Bradykinin / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability; D002448:Cell Adhesion; D002478:Cells, Cultured; D051356:Cortactin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008643:Mesentery / Q000098:blood supply*; D018613:Microscopy, Confocal; D062793:Occludin; D010972:Platelet Activating Factor / Q000378:metabolism; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors; D014699:Venules / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D001920:Bradykinin; D015820:Cadherins; D051356:Cortactin; D008246:Lysophospholipids; D008565:Membrane Proteins; D062793:Occludin; D010972:Platelet Activating Factor; D013110:Sphingosine; D020744:rac GTP-Binding Proteins; D000099152:Cadherin 5; C495870:Cttn protein, rat; C568985:OCLN protein, human; C568987:Ocln protein, rat; C060506:sphingosine 1-phosphate