Biology Reference
In-Depth Information
Zimmerman et al.
1990
). cGMP is produced by soluble and particulate guanylyl
cyclases (sGC and pGC), which are stimulated by nitric oxide or natriuretic
peptides, respectively. In vitro studies have shown that NO can improve barrier
function, presumably via activation of sGC and production of cGMP. Several
groups demonstrated this effect via the use of exogenous NO donors such as sodium
nitroprusside and DETA NONOate (Hempel et al.
1996
; Suttorp et al.
1996b
;
Westendorp et al.
1994
; Wong et al.
2004
). Others have used nitric oxide synthase
(NOS) inhibitors such as L-NAME to show that NO is required for maintaining
endothelial barrier function (Draijer et al.
1995a
; He et al.
1997b
; Liu and Sundqvist
1997
). In vivo, loss of NO via either genetic ablation of eNOS or treatment with
L-NAME resulted in increased endothelial permeability (Predescu et al.
2005
).
On the other hand, several groups have shown that NO can increase endothelial
permeability. For example, it was demonstrated that while NO donors and cGMP
can decrease permeability in resting endothelial cells, cells stimulated with iono-
mycin to increase permeability showed a further increase in permeability upon
addition of NO donors in vitro (Holschermann et al.
1997
). Furthermore, in an
ex vivo model using frog mesenteric venular microvessels, it was further demon-
strated that the ability of ionomycin to increase permeability is attenuated by NOS
inhibitors, suggesting a role of NO in increasing permeability (He et al.
1997a
).
Finally, in vivo models, including the same eNOS
mice, were used to show
that NO is involved in mediating increases of permeability under inflammatory
conditions (Bucci et al.
2005
; Hatakeyama et al.
2006
).
Like NO, the role of natriuretic peptides in regulating endothelial permeability is
also controversial. Five different groups studying endothelial permeability found
that atrial natriuretic peptide (ANP) decreases endothelial permeability (Baron et al.
1989
; Hempel et al.
1996
; Klinger et al.
2006
; Suttorp et al.
1996b
; Westendorp
et al.
1994
). On the other hand, ANP has also been shown to increase endothelial
permeability in vitro by one group (Holschermann et al.
1997
). In vivo, ANP
has also been shown to increase endothelial permeability (Tucker et al.
1992
;
Zimmerman et al.
1990
). This was further supported by the finding that endothelial-
specific ablation of the ANP receptor, guanylyl cyclase-A (GC-A), resulted in
decreased permeability in vivo (Sabrane et al.
2005
). Further complicating this
issue is the questionable involvement of PKG. For example, it was reported that
the barrier-enhancing effects of cGMP is PKG dependent (Moldobaeva et al.
2006
).
Others also found that PKG mediated the barrier regulating effects, but instead
of decreasing permeability, they found that PKG increased permeability
(Holschermann et al.
1997
). Additionally, the barrier-enhancing effects of cGMP
were reported to be PKG independent (Gupta et al.
2001
). Further complicating
the issue, it has been reported that the effects of cGMP are PKG dependent in
endothelial cells that express PKG, while they are independent in endothelial
cells that do not express PKG (Draijer et al.
1995a
,
b
). Thus, while it is fairly clear
that increased cAMP from endogenous membrane cyclases improves endothelial
barrier function, the role of cGMP, whether from stimulation of sGC by NO or
from pGC activated by ANP, has until recently remained unresolved.
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