Biology Reference
In-Depth Information
to have differential effects on endothelial permeability in part due to the various
effector molecules, crosstalk, and compartmentalization of cyclic nucleotide sig-
naling. PDEs, by controlling the amplitude, duration, and localization of cyclic
nucleotides, have been shown to play a critical role in regulating endothelial barrier
function. Thus, PDEs are attractive drug targets for the treatment of disease states
involving endothelial barrier dysfunction.
Keywords cAMP
cGMP
Endothelial barrier
Endothelial permeability
Phosphodiesterase
1
Introduction
One of the major functions of the endothelium is to act as an active barrier between
the circulating blood and the underlying vessel wall and tissues (Mehta and Malik
2006
; Michel and Curry
1999
; van Hinsbergh
1997
; van Nieuw Amerongen et al.
2001
; van Nieuw Amerongen and van Hinsbergh
2002
). The endothelium can
respond to a variety of signals to regulate the passage of proteins, fluid, and solutes
through the endothelial barrier. While oxygen, water, and solutes can pass through
this barrier via diffusion, channels, and slits in the cellular junctions, macromole-
cules can cross the endothelial barrier via three different mechanisms. These include
(1) transcellular passage through the cell via vesicles, (2) passage via pores in the
cell membrane usually formed by fused vesicles at the apical and basolateral
membrane, or (3) passage between endothelial cells paracellularly (Mehta and
Malik
2006
; van Hinsbergh
1997
). Dysregulation of endothelial barrier function is
characteristic of many diseases and pathological conditions including atherosclerosis,
asthma, tumor growth, edema, and sepsis (van Hinsbergh
1997
; van Nieuw Amer-
ongen and van Hinsbergh
2002
). Thus, understanding the mechanisms that regulate
endothelial permeability may allow for the development of drugs that can enhance
or decrease barrier function. In this chapter, we briefly summarize what is currently
known about the various mechanisms and signaling pathways that regulate endo-
thelial permeability by focusing on the role of cyclic nucleotide phosphodiesterases
as a potential drug target for the regulation of endothelial barrier function.
2 Transcellular and Paracellular Transport of Molecules
Through the Endothelial Barrier
Transport of macromolecules such as proteins, carbohydrates, and lipids across the
endothelial barrier occurs transcellularly or paracellulary. Most studies of trans-
cellular transport of macromolecules have focused on the role of caveolae and
vesiculo-vacuolar organelles (VVOs) as the transport vesicles. The proteins and
mechanisms involved share many similarities to those that regulate neuronal vesicle
