Mechanisms of Vascular Dysfunction in Vibration Injury

振动损伤中血管功能障碍的机制

基本信息

批准号：
7635844
负责人：
NICHOLAS A FLAVAHAN
金额：
$ 25.9万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7635844
关键词：
Mechanisms Vascular Dysfunction Vibration Injury

项目摘要

Hand-arm vibration syndrome (HAVS) causes considerable morbidity among workers exposed to vibration. The vascular component of HAVS is associated with increased vasoconstriction of finger digital arteries in response to cold exposure. The mechanisms contributing to this vascular disorder are unknown, which makes it difficult to monitor susceptibility or progression of the disease. A major goal of this proposal is to provide molecular insight this vascular dysfunction, so as to generate mechanism-based criteria that will improve diagnosis, monitoring and prevention of the disease. We demonstrate that cold-induced constriction of cutaneous arteries is caused by cold-induced generation of reactive oxygen species (ROS) from smooth muscle cell mitochondria that activate RhoA and Rho kinase, with the subsequent translocation of CC2C- adrenoceptors (cc2c-ARs) from the Golgi to the cell surface. Once there, these receptors respond to activation by norepinephrine and initiate cold-induced constriction. This pathway is targeted by vibration in cutaneous arteries. In a rat tail model that mimics the biodynamic response of human fingers, vibrationselectively increased constriction of isolated arteries to sympathetic stimulation and to aa-AR activation, which was abolished by OC2C-AR inhibition. Vibration also increased cold-induced constriction mediated by these receptors. The effects of vibration were associated with increased activity of Rho kinase, and with a ROS- dependent dysfunction of endothelial relaxation to acetylchpline. We propose that vibration initiates vascular disease by causing oxidant stress in cutaneous arteries resulting in endothelial cell dysfunction, activation of VSM Rho kinase and inappropriate mobilization of oi2c-ARs, increased sympathetic constriction and increased sensitivity to cold-induced constriction. Three Specific Aims are proposed to analyze the effects of acute and chronic exposure of cutaneous arteries to differing intensities of vibration exposure: Aim 1 will determine mechanisms underlyingthe vibration-induced increase in sympathetic vasoconstriction; Aim 2 will determine mechanisms underlyingthe vibration-induced increase in cold sensitivity of cutaneous arteries; and Aim 3 will determine the effects of vibration on endothelial cell function and vascular structure

手臂振动综合症 (HAVS) 在接触振动的工人中引起相当大的发病率。 HAVS 的血管成分与手指动脉的血管收缩增加有关。对寒冷暴露的反应。导致这种血管疾病的机制尚不清楚，这使得很难监测疾病的易感性或进展。该提案的一个主要目标是提供分子洞察这种血管功能障碍，从而产生基于机制的标准，以改善疾病的诊断、监测和预防。我们证明了寒冷引起的收缩皮肤动脉是由寒冷引起的平滑肌细胞产生活性氧（ROS）引起的激活 RhoA 和 Rho 激酶的肌肉细胞线粒体，随后发生 CC2C- 易位肾上腺素受体 (cc2c-AR) 从高尔基体到细胞表面。一旦到达那里，这些受体就会对激活做出反应去甲肾上腺素并启动寒冷引起的收缩。该通路是皮肤振动的目标动脉。在模仿人类手指生物动力学反应的鼠尾模型中，选择性振动增加孤立动脉的收缩以促进交感神经刺激和 aa-AR 激活，这是通过 OC2C-AR 抑制而消除。振动还增加了由这些介导的冷引起的收缩受体。振动的影响与 Rho 激酶活性的增加以及 ROS- 内皮松弛对乙酰胆碱的依赖性功能障碍。我们认为振动会引发血管通过在皮肤动脉中引起氧化应激而导致内皮细胞功能障碍、活化 VSM Rho 激酶和 oi2c-AR 的不适当动员、交感神经收缩增加和对寒冷引起的收缩的敏感性增加。提出了三个具体目标来分析其影响皮肤动脉急性和慢性暴露于不同强度的振动暴露：目标 1 将确定振动引起的交感血管收缩增加的机制；目标2将确定振动引起的皮肤动脉冷敏感性增加的机制；和目标 3 将确定振动对内皮细胞功能和血管结构的影响

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased oxidant activity mediates vascular dysfunction in vibration injury.

氧化活性增加介导振动损伤中的血管功能障碍。

DOI：
发表时间：
2009-01
期刊：
影响因子：
0
作者：
Hughes, Jennifer M;Wirth, Oliver;Krajnak, Kristine;Miller, Roger;Flavahan, Sheila;Berkowitz, Dan E;Welcome, Dan;Flavahan, Nicholas A
通讯作者：
Flavahan, Nicholas A

Cyclic stretch stimulates vascular smooth muscle cell alignment by redox-dependent activation of Notch3.

循环拉伸通过氧化还原依赖性激活 Notch3 来刺激血管平滑肌细胞排列。