Compensatory mechanisms influence hemostasis in setting of eNOS deficiency

• Published in: American journal of physiology. Heart and circulatory physiology 2005-04, Vol.288 (4), p.H1627-H1632
• Main Authors: Iafrati, Mark D, Vitseva, Olga, Tanriverdi, Kahraman, Blair, Price, Rex, Sybille, Chakrabarti, Subrata, Varghese, Sonia, Freedman, Jane E
• Format: Article
• Language: English
• Subjects: Animals; Carotid Artery Injuries - metabolism; Carotid Artery Injuries - physiopathology; Disease Models, Animal; Female; Fibrinolysis - physiology; Hemostasis - physiology; Male; Mice; Mice, Transgenic; Nitric Oxide - metabolism; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; P-Selectin - blood; Platelet Activation - physiology; Tissue Plasminogen Activator - genetics; von Willebrand Factor - metabolism; Weibel-Palade Bodies - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00819.2004

1 Department of Surgery, Tufts-New England Medical Center, Boston; and 2 Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Submitted 11 August 2004 ; accepted in final form 17 November 2004 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 wild-type mice. Paradoxically, the eNOS-deficient animals had a prolongation of time to occlusion compared with the wild-type mice ( P < 0.001). Consistent with this finding, plasma markers suggesting enhanced fibrinolysis [tissue plasminogen activator (t-PA) activity and antigen and D-dimer levels] were significantly elevated in eNOS-deficient animals. Vascular tissue expression of t-PA and platelet activity levels were not altered. In endothelial cells, t-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 t-PA) could be enhanced; this observation is also supported by increased von Willebrand factor 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 NO-dependent regulation of vascular homeostasis. Such compensatory mechanisms may partially explain the lack of spontaneous thrombosis, minimally elevated baseline blood pressure, and normal life span that are seen in animals deficient in a pivotal regulator of vascular patency. platelets; thrombosis; endothelial nitric oxide synthase; transgenic mice Address for reprint requests and other correspondence: M. D. Iafrati, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111 (E-mail: Miafrati{at}Tufts-NEMC.org )