Biology Reference
In-Depth Information
140
120
100
80
60
40
20
0
Thr (1 U/ml)
Fig. 2 Epac mediates some of the effects of cAMP on endothelial permeability. HUVEC
were stimulated with thrombin, thrombin + 10
m
M forskolin, or thrombin + 100
m
M8-CPT-
2
0
OMe-cAMP, and permeability assays were performed as described previously (Surapisitchat
et al.
2007
). Data represent mean (mean
SEM) from two independent experiments using HUVEC
isolated from two different umbilical cords
Epac to effect independent and complementary pathways to regulate endothelial
barrier function (Lorenowicz et al.
2008
).
While cAMP has been shown to inhibit increases in endothelial cell permeability
and various mechanisms have been proposed and demonstrated, recent reports from
the Steven's group demonstrate that the effects of cAMP on permeability are more
complex. Sayner et al. and Prasain et al. describe results that show a barrier-
disruptive effect of cAMP can be produced in the cytosol by activation of the
soluble adenylyl cyclases (Prasain et al.
2009
; Sayner et al.
2004
,
2006
). These
studies suggest that cytosolic-produced cAMP decreases barrier function, but
cAMP made by membrane adenylyl cyclases improves barrier function via PKA
and/or Epac. The concept of compartmentalization of cyclic nucleotide signaling
has been an area of increasing study of late (Fischmeister et al.
2006
; Houslay
2010
). It is possible that there are several cAMP “pools” that are responsible for the
regulation of endothelial permeability. While the role of cAMP in regulating
endothelial permeability has received substantial study, more work is needed to
understand the relative contribution of the cAMP effector molecules PKA and Epac
in mediating the effects of cAMP as well as the roles of compartmentalization of
cAMP and its regulation in endothelial barrier function.
5 The Role of cGMP in the Regulation of Endothelial
Barrier Function
The role of cGMP on endothelial barrier function is even more controversial than
that of cAMP. Both barrier-enhancing and impairing effects of cGMP have been
reported (Draijer et al.
1995a
; van Nieuw Amerongen and van Hinsbergh
2002
;
