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Cyclic GMP‐specific PDE5 in regulating pulmonary endothelial permeability
Author(s) -
Zhu Bing,
Xu Yan Chun,
Rich Thomas C,
Strada Samuel J
Publication year - 2009
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.23.1_supplement.965.2
Subject(s) - intracellular , permeability (electromagnetism) , endothelial stem cell , endothelium , ve cadherin , microbiology and biotechnology , chemistry , tight junction , vascular permeability , cell junction , thrombin , biology , cell , in vitro , biochemistry , immunology , endocrinology , platelet , membrane
Intracellular cGMP ([cGMP]i) regulates endothelial cell (EC) permeability. PDE5, an enzyme possessing cGMP hydrolytic activity, expresses discretely in pulmonary artery and microvascular ECs (PAECs/PMVECs). Indeed, without PDE5 expression, [cGMP]i in PMVECs is higher than it is in PAECs. Interestingly, PMVECs have tighter barrier junctions, with less permeability, than PAECs. However, the role of PDE5 in regulating endothelial barrier permeability is unknown. We questioned whether increases in [cGMP]i caused by decreasing PDE5 activity protects endothelial barrier junctions. Using labeled Dextran, we determined whether the permeability of ECs' monolayer is altered by PDE5 activity. Decrease of PDE5 activity in PAECs, either by siRNA or selective inhibitor, led to a decrease in barrier permeability. PDE5 inhibition also protected PAECs from a thrombin‐induced increases in permeability and barrier dysfunction. Overexpression of PDE5A1 in PMVECs reduced basal [cGMP]i. PDE5A1‐expressing cells showed increased basal permeability and thrombin‐triggered permeability which was not seen in wild‐type PMVECs. This cGMP‐regulated permeability requires PKG and its corresponding phosphorylation of VASP‐Ser239 and maintenance of cytoskeletal structure of F‐actin. Therefore, results suggest that PDE5 plays a key role in regulating endothelial barrier integrity in pulmonary artery (AHA 0665169).