Biology Reference
In-Depth Information
Regulation of Endothelial Barrier Function
by Cyclic Nucleotides: The Role
of Phosphodiesterases
James Surapisitchat and Joseph A. Beavo
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
2 Transcellular and Paracellular Transport of Molecules
Through the Endothelial Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
3 Signaling Pathways Shown to Regulate Endothelial Permeability . . . . . . . . . . . . . . . . . . . . . . . 196
4 The Role of cAMP in the Regulation of Endothelial Barrier Function . . . . . . . . . . . . . . . . . . 197
5 The Role of cGMP in the Regulation of Endothelial Barrier Function . . . . . . . . . . . . . . . . . . 199
6 Endothelial Cell Cyclic Nucleotide Phosphodiesterases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
7 The Role of Phosphodiesterases in the Regulation of Endothelial Permeability . . . . . . . . . 202
8 Crosstalk Between cGMP and cAMP: The Role of PDEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
9 Cyclic Nucleotide Pools in Endothelial Barrier Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
10 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Abstract The endothelium plays an important role in maintaining normal vascular
function. Endothelial barrier dysfunction leading to increased permeability and
vascular leakage is associated with several pathological conditions such as edema
and sepsis. Thus, the development of drugs that improve endothelial barrier func-
tion is an active area of research. In this chapter, the current knowledge concerning
the signaling pathways regulating endothelial barrier function is discussed with a
focus on cyclic nucleotide second messengers (cAMP and cGMP) and cyclic
nucleotide phosphodiesterases (PDEs). Both cAMP and cGMP have been shown
J. Surapisitchat
Department of Pharmacology, University of Washington School of Medicine, 1959 NE Pacific St.,
Box 357280, Seattle, WA 98195-7280, USA
and
McEwen Centre for Regenerative Medicine, University Health Network, 101 College Street,
Room 8-601, Toronto, ON, Canada, M5G 1L7
J.A. Beavo (
*
)
Department of Pharmacology, University of Washington School of Medicine, 1959 NE Pacific St.,
Box 357280, Seattle, WA 98195-7280, USA
e-mail: beavo@u.washington.edu
