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)在接触振动的工人中会导致相当大的发病率。 HAVS的血管成分与指、指动脉收缩增加有关。 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 很难监测这种疾病的易感性或进展情况。这项提案的一个主要目标是提供 分子洞察这种血管功能障碍，从而产生以机制为基础的标准，将会得到改善 疾病的诊断、监测和预防。我们证明了冷诱导的收缩 皮肤动脉是由寒冷诱导的光滑血管产生的活性氧引起的。 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素能受体(CC2C-ARs)。一旦到了那里，这些受体就会对激活做出反应 通过去甲肾上腺素和启动冷诱导收缩。这一途径被皮肤的振动作为靶点。 动脉。在模拟人类手指生物动力学反应的老鼠尾巴模型中，有选择地振动 离体动脉对交感神经刺激和AA-AR激活的收缩增加，这是 被OC2C-AR抑制所废除。振动也增加了由这些因素介导的冷引起的收缩 感受器。振动的影响与Rho激酶的活性增加有关，与ROS- 乙酰胆碱引起的内皮依赖性松弛功能障碍。我们认为振动会引发血管 通过在皮肤动脉引起氧化应激导致内皮细胞功能障碍，激活 VSM Rho激酶和不适当的o2c-Ars动员，增加交感神经收缩和 对冷致收缩的敏感度增加。提出了三个具体目标来分析 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 确定振动引起交感血管收缩增加的机制；目标2将 确定振动导致皮肤动脉冷敏感性增加的机制；以及 目标3将确定振动对内皮细胞功能和血管结构的影响