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VASCULAR ENDOTHELIAL FUNCTION DURING SYSTEMIC HYPOXIA

全身缺氧期间的血管内皮功能

基本信息

批准号：
6629067
负责人：
JOHN G WOOD
金额：
$ 24.78万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-03 至 2005-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6629067
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

项目摘要

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.

该提案旨在研究系统性缺氧对血管内皮功能的影响。活体显微镜技术将用于观察暴露于不同水平的激发 PO2 的完整、相对未受干扰的大鼠的微循环。虽然内皮细胞对缺血/再灌注的反应已被广泛研究，但系统性缺氧（例如高原暴露和急慢性肺部疾病）的影响。我们的初步研究表明，呼吸 10% O2 引起的缺氧会导致缺氧发生后几分钟内肠系膜和骨骼肌微静脉中的白细胞与内皮相互作用增加，随后出现白细胞外渗。尽管出现了普遍的、严重的内皮损伤，但大鼠在3周内适应的缺氧水平与未适应的大鼠中促进内皮功能障碍的水平相当，这表明微循环已适应。该提案的具体目标是： 1. 确定早期缺氧反应的机制：这将包括进一步表征初始血管内皮反应；鉴定这种现象的可能介质，包括活性氧、一氧化氮和脂质炎症介质；并鉴定参与该反应的白细胞-内皮粘附分子。 2. 评估内皮血管功能适应长期缺氧的潜在机制：这将包括研究活性氧、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，以及在因适应而改善组织氧合的过程中可能发挥的作用。这些研究将解决一个鲜为人知的课题，并应提供有关完整生物体应对全身缺氧的机制的重要新信息。