Biology Reference
In-Depth Information
cGMP signaling add to this growing list of examples in which alteration of PDE
expression and activity in response to physiological stimuli can lead to altered
cellular responses. Changes in PDE expression may change the “size and shape” of
the normal cyclic nucleotide pool to one that is pathologic. Understanding how
changes in PDE expression by pathological stimuli alter endothelial barrier function
will be important for the development of treatments of disease states involving
endothelial barrier dysfunction.
10 Conclusions
The last several years have been filled with new and exciting findings concerning
the role of cyclic nucleotides and PDEs in the regulation of endothelial barrier
function. Whereas less than ten years ago the dogma had been that cAMP improved
endothelial barrier function while the role of cGMP was debatable, today the role
of these two second messengers in endothelial permeability has been shown to
be highly dependent on the concentration and localization of these two second
messengers within the endothelial cell. PDEs have been shown to play a critical
role in regulating the amplitude, duration, and localization of cAMP and cGMP in
endothelial cells and thus regulate endothelial barrier function. The concept of
different subcellular pools of cAMP and cGMP, controlled by PDEs, regulating
different cellular functions is becoming increasingly important. Altered PDE expres-
sion in pathological states may alter these pools and thus the effects of these cyclic
nucleotides. Thus, understanding the role of PDEs in regulating cyclic nucleotide
signaling in normal and pathological endothelial functions may be important for the
development of drugs targeting specific PDEs in order to treat diseases that are
caused by endothelial dysfunction.
Acknowledgments The authors would like to thank the members of the Beavo lab for their
support over the course of these experiments. This work was funded by grants GM083926,
AR056221, and Foundation Leducq to J.A.B.
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