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Inhibition of human platelet reactivity by endothelium-derived relaxing
factor from human umbilical vein endothelial cells in suspension: blockade
of aggregation and secretion by an aspirin-insensitive mechanism
MJ Broekman, AM Eiroa and AJ Marcus
Department of Medicine, Department of Veterans Affairs Medical Center, New
York, NY.
To determine a role for endothelium-derived relaxing factor/nitric oxide
(EDRF/NO) in regulation of human platelet reactivity by human endothelial
cells (EC), we studied combined suspensions of human umbilical vein
endothelial cells (HU-VEC, passage 2 through 3) and washed human platelets.
Confluent HUVEC monolayers were treated with aspirin (1 mmol/L) to prevent
prostacyclin (PGI2) formation, washed, and harvested. Aspirin-treated
platelets alone (58 x 10(6)) were fully aggregated by thrombin at 0.05 U/mL
or more. In the presence of 10(6) HUVEC, however, platelet serotonin
release and aggregation in response to thrombin at doses as high as 0.5
U/mL were blocked. We demonstrated for the first time that inhibition of
aggregation and serotonin release, due to EDRF/NO, occurred in parallel.
HUVEC-dependent inhibition of platelet responsiveness was enhanced by
superoxide dismutase (SOD) and reversed by hemoglobin. The inhibitory
effect was also reversed by preincubation of HUVEC with
NG-monomethyl-L-arginine (NMA) or NG-nitro-L-arginine (NNA) through
competitive blockade of arginine metabolism. Pretreatment of platelets with
methylene blue indicated that EC-dependent inhibition of platelet
reactivity occurred through activation of platelet soluble guanylate
cyclase. When platelets and HUVEC were separated by a permeable membrane
and both cells were stimulated by thrombin, platelets remained
unresponsive. This indicated that inhibition was induced by a fluid-phase
mediator, independent of direct cell-cell contact. These data demonstrate
that EDRF/NO formation from L-arginine by human EC plays an important role
as an aspirin-insensitive fluid-phase inhibitor of human platelet
reactivity.
Volume 78,
Issue 4,
pp. 1033-1040,
08/15/1991
Copyright © 1991 by The American Society of Hematology
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