VASCULAR ENDOTHELIAL FUNCTION DURING SYSTEMIC HYPOXIA

本研究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完整的，相对不受干扰的大鼠，暴露于不同水平的激发PO2的微循环。虽然内皮对缺血/再灌注的反应已被广泛研究，但系统性缺氧（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诱导的缺氧在缺氧开始的几分钟内导致肠系膜和骨骼肌小静脉中白细胞内皮相互作用增加，随后是白细胞外渗。尽管出现了普遍的、严重的内皮损伤，但与未适应环境的大鼠相比，大鼠适应了3周的缺氧水平，从而促进了内皮功能障碍，这表明微循环的适应。本建议的具体目的是：1。确定对缺氧早期反应的机制：这将包括对初始血管内皮反应的进一步表征；确定这一现象可能的介质，包括活性氧、一氧化氮和脂质炎症介质；并鉴定白细胞内皮粘附分子参与这一反应。2. 为了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物种、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等因素所起的作用，以及适应所导致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主题，并应提供重要的新信息，利用完整的生物体应对全身性缺氧的机制。

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.