This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 101/8/811    most recent CIRCRESAHA.107.154229v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Surapisitchat, J. Articles by Beavo, J. A. Search for Related Content PubMed PubMed Citation Articles by Surapisitchat, J. Articles by Beavo, J. A. Related Collections Cell signalling/signal transduction Endothelium/vascular type/nitric oxide

(Circulation Research. 2007;101:811.)
© 2007 American Heart Association, Inc.

Cellular Biology

Differential Regulation of Endothelial Cell Permeability by cGMP via Phosphodiesterases 2 and 3

James Surapisitchat, Kye-Im Jeon, Chen Yan, Joseph A. Beavo

From the Department of Pharmacology (J.S., J.A.B.), University of Washington School of Medicine, Seattle; and Cardiovascular Research Institute (K.-I.J., C.Y.), University of Rochester, NY.

Correspondence to Joseph A. Beavo, PhD, University of Washington, Department of Pharmacology, 1959 NE Pacific St, Box 357280, Seattle, WA 98195-7280. E-mail beavo{at}u.washington.edu

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]--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- reversed the inhibition of permeability caused by low doses of ANP. As predicted, the effect of tumor necrosis factor- 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.

Key Words: phosphodiesterase • cGMP • endothelial permeability • TNF-

This article has been cited by other articles:

				R.C. Werthmann, K. von Hayn, V.O. Nikolaev, M.J. Lohse, and M. Bünemann Real-time monitoring of cAMP levels in living endothelial cells: thrombin transiently inhibits adenylyl cyclase 6 J. Physiol., August 15, 2009; 587(16): 4091 - 4104. [Abstract] [Full Text] [PDF]

				S. Kumar, X. Sun, S. Sharma, S. Aggarwal, K. Ravi, J. R. Fineman, and S. M. Black GTP cyclohydrolase I expression is regulated by nitric oxide: role of cyclic AMP Am J Physiol Lung Cell Mol Physiol, August 1, 2009; 297(2): L309 - L317. [Abstract] [Full Text] [PDF]

				T. M. A. Mohamed, D. Oceandy, S. Prehar, N. Alatwi, Z. Hegab, F. M. Baudoin, A. Pickard, A. O. Zaki, R. Nadif, E. J. Cartwright, et al. Specific Role of Neuronal Nitric-oxide Synthase when Tethered to the Plasma Membrane Calcium Pump in Regulating the {beta}-Adrenergic Signal in the Myocardium J. Biol. Chem., May 1, 2009; 284(18): 12091 - 12098. [Abstract] [Full Text] [PDF]

				E. P. Schmidt, M. Damarla, O. Rentsendorj, L. E. Servinsky, B. Zhu, A. Moldobaeva, A. Gonzalez, P. M. Hassoun, and D. B. Pearse Soluble guanylyl cyclase contributes to ventilator-induced lung injury in mice Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L1056 - L1065. [Abstract] [Full Text] [PDF]

				B. Schreier, S. Borner, K. Volker, S. Gambaryan, S. C. Schafer, P. Kuhlencordt, B. Gassner, and M. Kuhn The Heart Communicates with the Endothelium through the Guanylyl Cyclase-A Receptor: Acute Handling of Intravascular Volume in Response to Volume Expansion Endocrinology, August 1, 2008; 149(8): 4193 - 4199. [Abstract] [Full Text] [PDF]