Compensatory mechanisms influence hemostasis in setting of eNOS deficiency
Compensatory mechanisms influence hemostasis in setting of eNOS deficiency
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DOI：
10.1152/ajpheart.00819.2004
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发表时间：
2005-04-01
影响因子：
4.8
通讯作者：
Freedman, JE
中科院分区：
文献类型：
--
作者：
Iafrati, MD;Vitseva, O;Freedman, JE
血栓形成和出血之间的平衡受到仔细的调节。一氧化氮(NO)是这些过程的重要介体，因为它阻止了血小板与内皮细胞的黏附，并抑制了血小板的募集。尽管内皮型一氧化氮合酶(ENOS)缺陷小鼠的血管反应性降低和轻度高血压，但体内血栓形成并未被证实。为了确定内源性NO在止血中的作用，利用eNOS缺陷和野生型小鼠建立了颈动脉损伤和血栓形成模型。矛盾的是，与野生型小鼠相比，eNOS缺陷小鼠的闭塞时间延长(P<；0.001)。与这一发现一致的是，提示纤溶增强的血浆标志物[组织纤溶酶原激活物(t-PA)活性以及抗原和D-二聚体水平]在eNOS缺乏的动物中显著升高。血管组织t-PA表达和血小板活性水平无明显变化。在内皮细胞中，t-PA储存在webel-Palade小体中，这些储存颗粒的胞吐作用被NO抑制。因此，在没有NO的情况下，可以促进webel-Palade小体内容物(和t-PA)的释放；这一观察结果也得到了eNOS缺陷动物中von Willebrand因子水平增加的支持。综上所述，虽然eNOS缺乏减弱血管反应性和增加血小板募集，但它也与增强的纤溶作用有关，这是由于缺乏对Webel-Palade体内释放的NO依赖的抑制。这些过程突显了NO依赖调节血管内稳态的复杂性。这种代偿机制可能部分解释了在血管通畅的关键调节因子缺乏的动物中缺乏自发性血栓形成、基础血压轻微升高和正常寿命的原因。
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.