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1 Medicine, Boston University School of Medicine, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: freedmaj{at}bu.edu.
The balance between thrombosis and hemorrhage is carefully regulated. Nitric oxide (NO) is an important mediator of these processes as it prevents platelet adhesion to the
endothelium and inhibits platelet recruitment. Although endothelial NO synthase (eNOS)- deficient mice have decreased vascular reactivity and mild hypertension, enhanced thrombosis in vivo has not been demonstrated. To determine the role of endogenous NO in hemostasis, a
model of carotid arterial injury and thrombosis was performed using eNOS-deficient and wildtype
mice. Paradoxically, the eNOS-deficient animals had a prolongation of time to occlusion as compared to the wild-type mice (p<0.001). Consistent with this finding, plasma markers suggesting enhanced fibrinolysis (tissue plasminogen activator (
-PA) activity and antigen and Ddimer levels) were significantly elevated in eNOS-deficient animals. Vascular tissue expression
of -PA and platelet activity were not altered. In endothelial cells, -PA is stored in Weibel-
Palade bodies and exocytosis of these storage granules is inhibited by NO. Thus, in the absence of NO, release of Weibel-Palade body contents (and -PA) could be enhanced, an observation also supported by increased von Willebrand factor (vWF) levels observed in eNOS-deficient
animals. In summary, although eNOS deficiency attenuates vascular reactivity and increases platelet recruitment, it is also associated with enhanced fibrinolysis due to lack of NO-dependent inhibition of Weibel-Palade body release. These processes highlight the complexity of NOdependent
regulation of vascular homeostasis. Such compensatory mechanisms may partially explain the lack of spontaneous thrombosis, minimally elevated baseline blood pressure, and
normal lifespan seen in animals deficient in a pivotal regulator of vascular patency.
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