Differential regulation of endothelial cell permeability by cGMP via phosphodiesterases 2 and 3.
Endothelial barrier dysfunction leading to increased permeability and vascular leakage is an underlying cause of several pathological conditions, including edema and sepsis. Whereas cAMP has been shown to decrease endothelial permeability, the role of cGMP is controversial. Endothelial cells express cGMP-inhibited phosphodiesterase (PDE)3A and cGMP-stimulated PDE2A. Thus we hypothesized that the effect of cGMP on endothelial permeability is dependent on the concentration of cGMP present and on the relative expression levels of PDE2A and PDE3A. When cAMP synthesis was slightly elevated with a submaximal concentration of 7-deacetyl-7-(O-[N-methylpiperazino]-gamma-butyryl)-dihydrochloride-forskolin (MPB-forskolin), we found that low doses of either atrial natriuretic peptide (ANP) or NO donors potentiated the inhibitory effects of MPB-forskolin on thrombin-induced permeability. However, this inhibitory effect of forskolin was reversed at higher doses of ANP or NO. These data suggest that cGMP at lower concentrations inhibits PDE3A and thereby increases a local pool of cAMP, whereas higher concentrations cGMP activates PDE2A, reversing the effect. Inhibitors of PDE3A mimicked the effect of low-dose ANP on thrombin-induced permeability, and inhibition of PDE2A reversed the stimulation of permeability seen with higher doses of ANP. Finally, increasing PDE2A expression with tumor necrosis factor-alpha reversed the inhibition of permeability caused by low doses of ANP. As predicted, the effect of tumor necrosis factor-alpha on permeability was reversed by a PDE2A inhibitor. These findings suggest that the effect of increasing concentrations of cGMP on endothelial permeability is biphasic, which, in large part, is attributable to the relative amounts of PDE2A and PDE3A in endothelial cells.
Surapisitchat
James
J
University of Washington, Department of Pharmacology, 1959 NE Pacific St, Seattle, WA 98195-7280, USA.
Jeon
Kye-Im
KI
Yan
Chen
C
Beavo
Joseph A
JA
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000235:genetics / Q000502:physiology*; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517275:PDE2A protein, human; C517287:PDE3A protein, human; D006152:Cyclic GMP