VASCULAR ENDOTHELIAL FUNCTION DURING SYSTEMIC HYPOXIA

全身缺氧期间的血管内皮功能

• 批准号: 6351614
• 负责人: JOHN G WOOD
• 金额: $ 23.36万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-03 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6351614
• 关键词: environmental adaptation; free radical oxygen; heme oxygenase; hypoxia; intravital microscopy; laboratory rat; microcirculation; nitric oxide synthase; oxidative stress; oxygen tension; respiratory gas level; respiratory oxygen; vascular cell adhesion molecule; vascular endothelial growth factors; vascular endothelium

This proposal is directed to study the effect of systematic hypoxia on vascular endothelial function. The technique of intravital microscopy will be used to observe the microcirculation of intact, relatively undisturbed rats, exposed to different levels of inspired PO2. While the endothelial response to ischemia/reperfusion has been studied extensively, the effects of systematic hypoxia such as altitude exposure and acute and chronic pulmonary disease. Our preliminary studies indicate that hypoxia induced by breathing 10% O2 results in increased leukocyte-endothelial interaction in both mesentery and skeletal muscle venules within a few minutes of the onset of hypoxia, followed by leukocyte extravasation. In spite of what appears to be a generalized, severe endothelial injury, rats acclimatized for 3 weeks to comparable levels of hypoxia than that which promotes endothelial dysfunction in non-acclimatized rats, suggesting an acclimatization of the microcirculation. The specific aims of this proposal are: 1. To determine the mechanisms responsible for the early response to hypoxia: this will include further characterization of the initial vascular endothelial response; identification of the possible mediators of this phenomenon, including reactive oxygen species, nitric oxide and lipid inflammatory mediators; and identification of the leukocyte-endothelial adhesion molecules involved in this response. 2. To evaluate the potential mechanisms involve din the acclimatization of endothelial vascular function to prolonged hypoxia: this will include studies of the role played by factors such as reactive O2 species, up-regulation of inducible nitric oxide synthase, heme oxygenase-1 and vascular endothelial growth factor, as well as the possible role in this process of the improved tissue oxygenation that results from acclimatization. These studies will address a poorly understood subject and should provide significant new information on the mechanisms utilized by intact organisms to respond to systemic hypoxia.

本研究旨在研究全身低氧对血管内皮功能的影响。活体显微镜技术将用于观察处于不同水平吸入PO2的完整、相对未受干扰的大鼠的微循环。虽然血管内皮细胞对缺血/再灌注的反应已经得到了广泛的研究，但系统性低氧的影响，如高原暴露和急慢性肺部疾病。我们的初步研究表明，呼吸10%O2引起的缺氧导致肠系膜和骨骼肌小静脉内白细胞-内皮相互作用在缺氧开始后的几分钟内增加，随后白细胞渗出。尽管这似乎是一种普遍的、严重的内皮损伤，但大鼠在3周内适应了与未习服大鼠促进内皮功能障碍的水平相当的低氧，这表明微循环已习服。这项建议的具体目的是：1.确定早期对低氧反应的机制：这将包括对最初的血管内皮细胞反应的进一步表征；确定这种现象的可能介质，包括活性氧物种、一氧化氮和脂类炎症介质；以及确定参与这种反应的白细胞-内皮黏附分子。2.评估内皮血管功能对长时间低氧习服的可能机制：包括研究反应性氧自由基、诱导型一氧化氮合酶、血红素加氧酶-1和血管内皮生长因子上调等因素所起的作用，以及习服引起的组织氧合改善在这一过程中的可能作用。这些研究将解决一个知之甚少的问题，并应提供有关完整生物体用来应对系统性缺氧的机制的重要新信息。