Mechanisms of Vascular Dysfunction in Vibration Injury

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血管收缩增加有关，以应对寒冷暴露。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。本提案的主要目标是提供血管功能障碍的分子洞察力，从而产生基于机制的标准，从而提高疾病的诊断、监测和预防。我们证明，冷诱导的皮肤动脉收缩是由平滑肌细胞线粒体冷诱导产生的活性氧（ROS）引起的，活性氧激活RhoA和Rho激酶，随后alpha2Cadrenoceptors （alpha2c-ARs）从高尔基体转移到细胞表面。一旦到达那里，这些受体对去甲肾上腺素的激活作出反应，并启动冷诱导收缩。这一途径是通过皮肤动脉的振动来定位的。在模拟人类手指生物动力学反应的大鼠尾巴模型中，振动选择性地增加了孤立动脉对交感刺激和alpha2-AR激活的收缩，而alpha2C-AR抑制则消除了这种收缩。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激酶活性增加有关，并与ros依赖性内皮舒张功能障碍有关。我们认为振动引发血管疾病的途径是引起皮肤动脉的氧化应激，导致内皮细胞功能障碍、VSM Rho激酶的激活和alpha2c-ARs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。提出了三个特定目的来分析急性和慢性皮肤动脉暴露于不同强度振动的影响：目的1将确定振动诱导交感血管收缩增加的机制；目的2将确定振动引起皮肤动脉冷敏感性增加的机制；Aim 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.