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Differential Regulation of Endothelial Cell Permeability by cGMP via Phosphodiesterases 2 and 3
Author(s) -
Surapisitchat James,
Jeon KyeIm,
Yan Chen,
Beavo Joseph A.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1165-c
Subject(s) - phosphodiesterase , phosphodiesterase 3 , permeability (electromagnetism) , atrial natriuretic peptide , chemistry , endothelial stem cell , pde10a , medicine , nitric oxide , stimulation , vascular permeability , inhibitory postsynaptic potential , endocrinology , in vitro , biology , enzyme , biochemistry , membrane
Increased endothelial permeability is an underlying cause of several pathological conditions. While cAMP decreases endothelial permeability, the role of cGMP is controversial. Endothelial cells express cGMP‐inhibited phosphodiesterase 3A (PDE3A) and cGMP‐stimulated phosphodiesterase 2A (PDE2A). Thus we hypothesized that the effect of cGMP on endothelial permeability depends on the concentration of cGMP present and on the ratio of PDE2A to PDE3A. We found that low doses of atrial natriuretic peptide (ANP) or nitric oxide (NO) donors potentiated the inhibitory effects of cAMP on thrombin‐induced permeability. This inhibitory effect of cAMP was reversed at higher doses of ANP or NO. Inhibition of PDE3A mimicked the effect of low doses of ANP on thrombin‐induced permeability supporting the role of PDE3A in mediating the inhibitory effects of ANP. Inhibition of PDE2A reversed the stimulation of permeability seen with higher doses of ANP supporting the role of PDE2A. Increasing PDE2A expression by TNF alpha reversed the inhibition of permeability caused by low doses of ANP, an effect reversed by PDE2A inhibition. These findings suggest that the biphasic effects of cGMP on endothelial permeability are due in large part to the ratio of PDE2A to PDE3A and to the concentration of cGMP present and likely resolve much of the controversy about the role of cGMP on endothelial permeability. Supported by NIH grant DK21723.