Mechanisms of Vascular Dysfunction in Vibration Injury

振动损伤中血管功能障碍的机制

• 批准号: 7491610
• 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
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491610
• 关键词: Mechanisms; Vascular; Dysfunction; Vibration; Injury

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

手臂振动综合征（HAVS）导致暴露于振动的工人之间的发病率很高。 HAV的血管成分与手指数字动脉的血管收缩增加有关 对冷暴露的反应。导致这种血管疾病的机制未知，这使得 很难监测疾病的敏感性或进展。该提议的主要目标是提供 分子见解这种血管功能障碍，以生成基于机制的标准，以改善 诊断，监测和预防疾病。我们证明了冷诱导的收缩 皮肤动脉是由光滑产生的活性氧（ROS）引起的 激活RhoA和Rho激酶的肌肉细胞线粒体随后易位CC2C- 从高尔基体到细胞表面的肾上腺受体（CC2C-ARS）。到达那里后，这些受体对激活做出反应 通过去甲肾上腺素并开始冷诱导的收缩。该途径是针对皮肤振动的目标 动脉。在模仿人手指的生物动力反应的大鼠尾巴模型中，振动性 孤立动脉对交感神经刺激和AA-AR激活的收缩增加了，这是 被OC2C-AR抑制作用。振动还增加了由这些振动介导的冷诱导收缩 受体。振动的影响与Rho激酶的活性增加有关，并且与ROS- 内皮放松对乙酰氯chpline的依赖功能障碍。我们提出振动会引发血管 通过在皮肤动脉中引起氧化应激，导致内皮细胞功能障碍，激活 VSM Rho激酶和不当动员OI2C-ARS，同情的收缩增加和 对冷诱导收缩的敏感性提高。提出了三个具体目标来分析 皮肤动脉急性和长期暴露于不同的振动暴露强度：AIM 1 Will 确定振动引起的交感神经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 AIM 3将确定振动对内皮细胞功能和血管结构的影响