© 1999 American Heart Association, Inc.
Original Contribution |
Deficient Platelet-Derived Nitric Oxide and Enhanced Hemostasis in Mice Lacking the NOSIII Gene
From the Departments of Pharmacology and Medicine (J.E.F.), Georgetown University Medical Center, Washington, DC; Whitaker Cardiovascular Institute and Evans Department of Medicine (R.S., E.M.B., J.L.), Boston University School of Medicine, Mass; Maine Medical Center Research Institute (K.A., C.K.), South Portland; and Cardiovascular Research Center (P.L.H.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass.
Correspondence to Jane E. Freedman, Med-Dent Bldg, Room NE 403, Georgetown University Medical Center, 3900 Reservoir Rd, NW, Washington, DC 20007. E-mail freedmaj{at}gunet.georgetown.edu
Abstract—Endothelial
nitric oxide synthase (eNOS) has been identified in human
platelets. Although platelet-derived nitric oxide (NO) has been
shown to inhibit platelet recruitment in vitro, its role in the
regulation of the hemostatic response in vivo has not been
characterized. To define the role of platelet-derived NO in vivo,
we studied mice that lacked a functional eNOS gene (NOSIII). Surface
P-selectin expression in platelets from eNOS-deficient mice was not
significantly altered; however, bleeding times were markedly decreased
in eNOS-deficient versus wild-type mice (77.2±3 versus 133.4±3
seconds, P<0.00005). To determine the contribution of
endothelium- versus platelet-derived NO to the
bleeding time, isolated platelets from either eNOS-deficient or
wild-type mice were transfused into a thrombocytopenic eNOS-deficient
mouse and the bleeding time was measured. The bleeding times in mice
transfused with eNOS-deficient platelets were significantly
decreased compared with mice transfused with wild-type platelets
(
bleeding time, -24.6±9.1 and -3.4±5.3 seconds, respectively;
P<0.04). Platelet recruitment was studied by
measuring serotonin release from a second recruitable
population of platelets that were added to stimulated platelets
at the peak of NO production. There was 40.3±3.7% and
52.0±2.1% serotonin release for platelets added to
wild-type or eNOS-deficient platelets, respectively
(P<0.05). In summary, mice that lacked eNOS had
markedly decreased bleeding times even after
endothelial NO production was controlled. These
data suggest that the lack of platelet-derived NO alters in vivo
hemostatic response by increasing platelet recruitment. Thus, these
data support a role for platelet-derived NO production in
the regulation of hemostasis.
Key Words: selectin • mice • platelet • nitric oxide synthase
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