Mechanisms of Vascular Dysfunction in Vibration Injury

手臂振动综合征（HAVS）在接触振动的工人中引起相当大的发病率。 HAVS的血管成分与手指指动脉对冷暴露的反应性血管收缩增加有关。导致这种血管疾病的机制尚不清楚，这使得难以监测疾病的易感性或进展。该提案的一个主要目标是提供这种血管功能障碍的分子见解，从而产生基于机制的标准，这将改善疾病的诊断，监测和预防。我们证明，冷诱导收缩的皮肤动脉是由冷诱导产生的活性氧（ROS）从平滑肌细胞线粒体，激活RhoA和Rho激酶，随后易位的α 2钙调素受体（α 2c-ARs）从高尔基体的细胞表面。一旦到达那里，这些受体就会对去甲肾上腺素的激活做出反应，并启动冷诱导的收缩。这条通路是皮肤动脉中振动的目标。在模拟人类手指生物动力学反应的大鼠尾部模型中，振动选择性地增加了交感神经刺激和α 2-AR激活的孤立动脉的收缩，这被α 2C-AR抑制所消除。振动也增加了由这些受体介导的冷诱导收缩。振动的影响与Rho激酶活性的增加有关，并且与ROS依赖的内皮舒张功能障碍有关。我们认为振动通过引起皮肤动脉中的氧化应激而引发血管疾病，从而导致内皮细胞功能障碍、VSM Rho激酶的激活和α 2c-AR的不适当动员、交感神经收缩增加和对冷诱导收缩的敏感性增加。提出了三个具体的目的来分析不同强度振动暴露对皮肤动脉的急性和慢性暴露的影响：目的1将确定振动诱导的交感血管收缩增加的潜在机制：目的2将确定振动诱导的皮肤动脉冷敏感性增加的潜在机制;目标3将确定振动对内皮细胞功能和血管结构的影响。

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 alpha2Cadrenoceptors (alpha2c-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, vibration selectively increased constriction of isolated arteries to sympathetic stimulation and to alpha2-AR activation, which was abolished by alpha2C-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 alpha2c-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 underlying the vibration-induced increase in sympathetic vasoconstriction; Aim 2 will determine mechanisms underlying the 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.