Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase
Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase
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DOI：
10.1089/neu.2015.4340
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发表时间：
2017-01-01
影响因子：
4.2
通讯作者：
Freeman, Kalev
中科院分区：
文献类型：
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作者：
Villalba, Nuria;Sackheim, Adrian M.;Freeman, Kalev
内皮功能障碍是许多慢性疾病的标志，包括糖尿病和长期高血压。我们发现，急性创伤性脑损伤（TBI）导致大鼠肠系膜动脉内皮功能障碍。TBI后24小时，由于一氧化氮（NO）的产生受损，内皮依赖性扩张大大减少。与内皮型NO合酶（eNOS）竞争共同底物L-精氨酸的精氨酸氧化酶的活性在动脉中也显著增加，表明精氨酸氧化酶介导的L-精氨酸耗竭是NO产生减少的基础。与此一致，通过外源性应用l-精氨酸或抑制精氨酸酶恢复底物可恢复内皮功能。此外，在内皮细胞和血浆中检测到活性氧产生增加的证据，这是L-精氨酸饥饿依赖性eNOS解偶联的结果。总的来说，我们的研究结果表明TBI后远端血管床的内皮功能障碍，表现为内皮依赖性血管舒张功能受损，血管紧张素转换酶活性增加，NO生成减少，O-2生成增加。我们的结论是，血管有一个“分子记忆”的神经创伤，损伤后24小时，由于血管内皮细胞的功能变化，这些影响是相关的理解全身炎症反应，发生后TBI，即使在没有多发性创伤。
Endothelial dysfunction is a hallmark of many chronic diseases, including diabetes and long-term hypertension. We show that acute traumatic brain injury (TBI) leads to endothelial dysfunction in rat mesenteric arteries. Endothelial-dependent dilation was greatly diminished 24 h after TBI because of impaired nitric oxide (NO) production. The activity of arginase, which competes with endothelial NO synthase (eNOS) for the common substrate l-arginine, were also significantly increased in arteries, suggesting that arginase-mediated depletion of l-arginine underlies diminished NO production. Consistent with this, substrate restoration by exogenous application of l-arginine or inhibition of arginase recovered endothelial function. Moreover, evidence for increased reactive oxygen species production, a consequence of l-arginine starvation-dependent eNOS uncoupling, was detected in endothelium and plasma. Collectively, our findings demonstrate endothelial dysfunction in a remote vascular bed after TBI, manifesting as impaired endothelial-dependent vasodilation, with increased arginase activity, decreased generation of NO, and increased O-2-production. We conclude that blood vessels have a "molecular memory'' of neurotrauma, 24 h after injury, because of functional changes in vascular endothelial cells; these effects are pertinent to understanding the systemic inflammatory response that occurs after TBI even in the absence of polytrauma.