Vascular endothelial dysfunction in β-thalassemia occurs despite increased eNOS expression and preserved vascular smooth muscle cell reactivity to NO.
Vascular endothelial dysfunction in β-thalassemia occurs despite increased eNOS expression and preserved vascular smooth muscle cell reactivity to NO.
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DOI：
10.1371/journal.pone.0038089
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Cloutier G
中科院分区：
文献类型：
--
作者：
Stoyanova E;Trudel M;Felfly H;Lemsaddek W;Garcia D;Cloutier G
遗传性β地中海贫血主要病症需要终身定期输血。输血相关的铁超载与心血管并发症的发生有关，包括心脏功能障碍和血管异常。通过使用未输血的重型β地中海贫血小鼠模型，我们测试了这样的假设：尽管不进行治疗，血管内皮功能障碍、动脉结构及其机械特性也会发生改变。离体评估血管功能和结构。与对照组相比，β地中海贫血小鼠的肠系膜阻力动脉中乙酰胆碱的内皮依赖性血管舒张作用减弱，而内皮非依赖性血管舒张剂（硝普钠）产生了类似的血管扩张，表明内皮细胞损伤，平滑肌细胞对一氧化氮（NO）的反应性得以保留。虽然这些发现表明 NO 生物利用度降低，但蛋白质印迹显示β-地中海贫血中主动脉内皮 NO 合酶 (eNOS) 的表达升高。颈总动脉的血管重塑显示内侧弹性蛋白含量增加。在等压条件下，β-地中海贫血小鼠的颈动脉由于血管壁的结构变化而表现出壁应力降低和软化。在未输血的β地中海贫血小鼠中发现了复杂的血管病变，其特征是颈动脉结构改变和阻力小动脉内皮功能障碍，这可能归因于尽管血管eNOS表达增强，但NO生物利用度降低。
The hereditary β-thalassemia major condition requires regular lifelong blood transfusions. Transfusion-related iron overloading has been associated with the onset of cardiovascular complications, including cardiac dysfunction and vascular anomalies. By using an untransfused murine model of β-thalassemia major, we tested the hypothesis that vascular endothelial dysfunction, alterations of arterial structure and of its mechanical properties would occur despite the absence of treatments. Vascular function and structure were evaluated ex vivo. Compared to the controls, endothelium-dependent vasodilation with acetylcholine was blunted in mesenteric resistance arteries of β-thalassemic mice while the endothelium-independent vasodilator (sodium nitroprusside) produced comparable vessel dilation, indicating endothelial cell impairment with preserved smooth muscle cell reactivity to nitric oxide (NO). While these findings suggest a decrease in NO bioavailability, Western blotting showed heightened expression of aortic endothelial NO synthase (eNOS) in β-thalassemia. Vascular remodeling of the common carotid arteries revealed increased medial elastin content. Under isobaric conditions, the carotid arteries of β-thalassemic mice exhibited decreased wall stress and softening due to structural changes of the vessel wall. A complex vasculopathy was identified in untransfused β-thalassemic mice characterized by altered carotid artery structure and endothelial dysfunction of resistance arterioles, likely attributable to reduced NO bioavailability despite enhanced vascular eNOS expression.
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