Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels.
Platelet accumulation at sites of vascular injury is the primary event in arterial thrombosis. Initial platelet accrual into thrombi is mediated by interactions of platelet adhesion receptors with ligands on the injured endothelium or in the sub-endothelial matrix. The role of intracellular signals in initial platelet accumulation at sites of endothelial injury, however, is the subject of debate. We have used a newly discovered inhibitor of phosphodiesterase 3A (PDE3A) and the well-characterized PDE3A inhibitor, cilostazol, to modulate 3',5'-cyclic adenosine monophosphate (cAMP) levels in an in vivo model that enables the kinetic analysis of platelet accumulation. These studies demonstrate that elevation of basal cAMP levels results in an overall decline in platelet accumulation at the site of vascular injury. In particular, the initial rate of accumulation of platelets is inhibited by elevation of cAMP. Analysis of the kinetics of individual platelets at injury sites using intravital microscopy demonstrates that cAMP directs the rate at which platelets attach to and detach from thrombi. These studies demonstrate that cAMP in circulating platelets controls attachment to and detachment from sites of arteriolar injury. Thus, the status of the intracellular signaling machinery prior to engagement of platelet receptors influences the rate of platelet accumulation during thrombus formation.
Sim
Derek S
DS
Center for Hemostasis and Thrombosis Research, Beth Israel Deaconess Medical Center, 41 Ave Louis Pasteur, Boston, MA 02115, USA.
Merrill-Skoloff
Glenn
G
Furie
Barbara C
BC
Furie
Bruce
B
Flaumenhaft
Robert
R
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006801:Humans; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000187:drug effects* / Q000502:physiology*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology; D013927:Thrombosis / Q000378:metabolism* / Q000503:physiopathology
C483539:JF959602; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D013777:Tetrazoles; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human; C517289:Pde3a protein, mouse; D000077407:Cilostazol