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Sudies on cyclic AMP in vascular endothelial cells: a target for new drugs against inflamation, atherosclerosis and thrombosis

Objective




Vascular endothelial cells have multiple functions: they
provide a non-thrombogenic surface, control microvascular
permeability, release factors which inhibit platelet
activation and relax vascular smooth muscle (prostacyclin,
nitric oxide) and modulate the proliferation of vascular -
smooth muscle cells... The concentration of cytosolic Ca2+
plays a crucial role in the control of several of these
functions: a rise of cytosolic Ca2+ stimulates the release
of prostacyclin and nitric oxide and induces cell
contraction, resulting in an increased permeability. More
recently, the potential importance of cyclic AMP in the
control of endothelial cell functions has emerged. Cyclic
AMP inhibits endothelial cell contraction and enhances the
barrier property of the endothelium. It stimulates the
expression of thrombomodulin on the surface of endothelial
cells, amplifies the release of tissue-plasminogen
activator (t-PA) and inhibits the secretion of an inhibitor
of t-PA. It also inhibits the synthesis of an endothelial
form of platelet-derived growth factor (PDGF). Therefore
it seems that agents which would increase the level of
cyclic AMP in endothelial cells might have a therapeutic
potential, in various pathological conditions. Enhancement
of barrier properties will decrease inflammatory exudates.
The stimulation of anticoagulant and fibrinolytic
mechanisms would be beneficial for the prevention of
thrombosis. Finally, the inhibition of PDGF synthesis
could be of value for the prevention of atherosclerosis.
The purpose of the present project is to investigate in
greater detail the mechanisms which control the level of
cyclic AMP in vascular endothelial cells - in particular
the role of H2 and P2 receptors - as well as the functional
consequences of increases in cyclic AMP level, in
particular on endothelial cell proliferation and on the
release of prostacyclin.

Coordinator

UNIVERSITE LIBRE DE BRUXELLES
Address
808,Route De Lennik 808 Campus Erasme - Building C
1070 Bruxelles
Belgium

Participants (1)

Centre de Recherches Jacques Logeais
France
Address
15 Rue Denis Papin
78190 Trappes