p42/44MAPK regulates baseline permeability and cGMP-induced hyperpermeability in endothelial cells.
We tested the hypothesis that p42/44MAPK and p38MAPK (mitogen-activated protein kinases; MAPK) signaling pathways regulate endothelial cell permeability to macromolecules. Passage 2-4 human umbilical vein endothelial cells (HUVEC) were grown to confluence on fibronectin-coated Snapwell membranes. The flux of fluorescein isothiocyanate-labeled dextran-70 across the HUVEC monolayers served to determine permeability. Application of 1 mM 8-bromo 3' 5'-cyclic guanosine monophosphate (8-Br-cGMP) increased permeability from 7.0 +/- 1.6 x 10(-6) to 12.5 +/- 2.8 x 10(-6) cm/s (P < 0.05). Pretreatment of HUVEC for 60 min with a selective p42/44MAPK inhibitor (AG126 at 2.7 and 27 microM) blocked 8-Br-cGMP-induced hyperpermeability. However, inhibition of p38MAPK (SB203580 at 0.6 microM) did not influence the cGMP-induced hyperpermeability response. AG126, administered at 27 microM, decreased baseline permeability from 7.9 +/- 0.5 x 10(-6) to 5.9 +/- 0.5 x 10(-6) cm/s (P < 0.05). Our results indicate that the p42/44MAPK signaling pathway is important in the regulation of baseline permeability and cGMP-induced hyperpermeability.
Varma
Shubha
S
Program in Vascular Biology, Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103-2714, USA.
Breslin
Jerome W
JW
Lal
Brajesh K
BK
Pappas
Peter J
PJ
Hobson
Robert W
RW
Durán
Walter N
WN
D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology
D004791:Enzyme Inhibitors; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D006152:Cyclic GMP