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(Koga et al.
1995
;Miroetal.
2000
; Seybold et al.
2005
). The reasons for the
differences in expression of PDEs in endothelial cells of different origins and in
response to different stimuli are not well understood. Many of these presumed
differences may relate to differences in passage number of the cells being compared.
7 The Role of Phosphodiesterases in the Regulation
of Endothelial Permeability
Since cAMP and cGMP play significant and sometimes conflicting roles in endothe-
lial barrier function, endothelial cell PDEs may play critical roles in the regulation of
endothelial permeability. The expression of cGMP-activated PDE2, cGMP-inhibited
PDE3, cAMP-specific PDE4, and cGMP-specific PDE5 by endothelial cells may
allow for differential regulation of barrier function by different PDEs. For example,
we have recently demonstrated that cGMP elevating agents such as ANP and NO
have biphasic effects on cAMP inhibition of thrombin-induced endothelial perme-
ability (Surapisitchat et al.
2007
). The reason for the biphasic actions of cGMP on
cAMP inhibition of thrombin-induced endothelial permeability is due to differen-
tial regulation of PDE2 and PDE3 by cGMP. Furthermore, altering the expression
levels of PDE2 and PDE3 in endothelial cells can alter the effect of cGMP on
endothelial permeability as is seen upon stimulation of the cells by TNF-
a
(Fig.
3
).
These results likely explain many of the conflicting results reported in the literature
concerning the actions of cGMP on endothelial permeability and suggest important
High ANP, NO
Low ANP, NO
High cGMP
Low cGMP
TNF-
α
PDE3
PDE2
cAMP
cAMP
Endothelial
permeability
Endothelial
permeability
Fig. 3 Proposed model of the effect of cGMP on endothelial cell permeability. cGMP generated
by NO or ANP stimulation can effect endothelial permeability in several ways. cGMP can inhibit
PDE3 leading to increased cAMP in the endothelial cell and decreased permeability. cGMP can
also activate PDE2 leading to decreased cAMP and increased permeability. The concentration of
cGMP within the cell plays a central role in whether the dominant effect is due to PDE3 inhibition
(low cGMP) or PDE2 activation (high cGMP). TNF-
a
can increase the amount of PDE2 expressed
in the endothelial cell and thus alter the response of the cell to cGMP and permeability (from
Surapisitchat et al.
2007
)
