Arnal J F, Dinh-Xuan A T, Pueyo M, Darblade B, Rami J
INSERM U397 et Laboratoire de Physiologie, CHU Rangueil, Toulouse, France.
Cell Mol Life Sci. 1999 Jul;55(8-9):1078-87. doi: 10.1007/s000180050358.
In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascular smooth muscle cells in response to acetylcholine is dependent on the anatomical integrity of the endothelium. Endothelium-derived relaxing factor was identified 7 years later as the free radical gas nitric oxide (NO). In endothelium, the amino acid L-arginine is converted to L-citrulline and NO by one of the three NO synthases, the endothelial isoform (eNOS). Shear stress and cell proliferation appear to be, quantitatively, the two major regulatory factors of eNOS gene expression. However, eNOS seems to be mainly regulated by modulation of its activity. Stimulation of specific receptors to various agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine, thrombin) increases eNOS enzymatic activity at least in part through an increase in intracellular free Ca2+. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although the precise mechanisms activating the enzyme remain to be elucidated. Phosphorylation and subcellular translocation (from plasmalemmal caveolae to the cytoskeleton or cytosol) are probably involved in these regulations. Although eNOS plays a major vasodilatory role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production could be responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be promoted by several risk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty streak infiltration of the neointima). Several mechanisms probably contribute to this decrease in NO bioavailability. Finally, a defect in NO generation contributes to the pathophysiology of pulmonary hypertension. Elucidation of the mechanisms of eNOS enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology of endothelial dysfunction, and could provide insights for new therapies, particularly in hypertension and atherosclerosis.
1980年，弗奇戈特和扎瓦茨基证明，血管平滑肌细胞对乙酰胆碱的反应性舒张依赖于内皮的解剖学完整性。7年后，内皮源性舒张因子被确定为自由基气体一氧化氮（NO）。在内皮中，氨基酸L-精氨酸通过三种一氧化氮合酶之一——内皮型一氧化氮合酶（eNOS），转化为L-瓜氨酸和NO。从数量上看，剪切应力和细胞增殖似乎是eNOS基因表达的两个主要调节因子。然而，eNOS似乎主要通过其活性的调节来调控。刺激特定受体以应对各种激动剂（如缓激肽、5-羟色胺、腺苷、ADP/ATP、组胺、凝血酶）至少部分通过增加细胞内游离钙离子浓度来提高eNOS酶活性。然而，机械刺激剪切应力似乎再次成为eNOS活性的主要刺激因素，尽管激活该酶的确切机制仍有待阐明。磷酸化和亚细胞易位（从质膜小窝到细胞骨架或细胞质）可能参与了这些调控。尽管eNOS在血管运动控制中发挥主要的血管舒张作用，但迄今为止尚未证明内皮NO生成缺陷会导致人类高血压。相反，已知几种危险因素（如吸烟、糖尿病、高胆固醇血症）会促进内皮依赖性血管舒张缺陷，并且它也是动脉粥样硬化（新内膜的脂肪条纹浸润）的结果。几种机制可能导致了NO生物利用度的降低。最后，NO生成缺陷促成了肺动脉高压的病理生理学。阐明eNOS酶活性和NO生物利用度的机制将有助于我们理解血管运动的生理学和内皮功能障碍的病理生理学，并可能为新的治疗方法提供思路，特别是在高血压和动脉粥样硬化方面。
