ENDOTHELIAL RESPONSE TO HYPOXIA

低氧/低氧血症（H），发生在广泛的心肺 和血管疾病在围产期有特别严重的后果， 期 内皮细胞（EC），最直接地受到环境的影响， 扰动，快速响应止血功能的改变 重要的血管内稳态，并通过设置在运动补偿 促进适应缺氧的机制。 的首要目标 这一提议旨在阐明H快速调节的机制， EC表面的特性最终有利于促凝血剂 最终导致血栓形成的事件。 这项建议 是基于初步研究表明，H诱导释放血栓前 vonWillebrand脂肪或来自EC，减少EC表面表达的 抗凝辅因子血栓调节蛋白，并诱导易位的 中性粒细胞粘附分子P-选择素至EC表面（结合/活化 白细胞损伤内皮细胞，并引发 内皮下）。 这一假设将在细胞培养中进行检验， 动物模型 因为我们以前的工作表明， cGMP抑制H诱导的白细胞结合， 其升高细胞内cGMP水平以阻断P-选择素表达， 作为一种潜在的保护性治疗干预进行研究。 的 第二个目的是研究H介导的白细胞介素6（IL-6）a的诱导作用， 具有抗炎和神经保护特性的细胞因子， 在缺氧时促进细胞存活。 这些实验 将研究IL-6表达增强的分子机制， H在启动子水平，基于我们最近的发现，NF-IL-6 启动子在H. 我们还将 说明IL-6在肺和肺纤维化模型中的潜在保护作用， 使用野生型和缺失突变型IL-6转基因的脑缺血 小鼠 项目五的工作将与 （一）我们将协助进行实验，以确定 H诱导的促肾上腺皮质激素释放增加的机制 胎盘中的激素表达（Goland）;以及（ii）我们将参与 在羊（丹尼尔博士）和狒狒模型（斯塔克博士）的胎盘 缺血，以确定我们的研究中确定的机制是否有效 在这些与围产期学相关的环境中。 通过体外和体内研究相结合，涉及项目V 及其与PERC中其他项目的互动，我们寻求 实现长期目标，了解对H的反应如何 干扰细胞功能，并带来关键的适应， 在缺氧的情况下存活。

Hypoxia/hypoxemia (H) which occurs in a wide spectrum of cardiopulmonary and vascular disorders has especially severe consequences in the perinatal period. Endothelial cells (ECs), most immediately subject to environmental perturbation, rapidly respond with alterations in hemostatic functions important in vascular homeostasis, and by setting in motion compensatory mechanisms facilitating adaptation to oxygen deprivation. The first aim of this proposal is to elucidate mechanisms through which H rapidly modulates the character of the EC surface to one which ultimately favors procoagulant events leading ultimately to the development of thrombosis. This proposal is based on pilot studies showing the H induces release of prothrombotic von Willebrand fat or from ECs, decreases EC surface expression of the anticoagulant cofactor thrombomodulin, and induces translocation of the neutrophil adherence molecule P-selectin to the EC surface (bound/activated leukocytes damage the endothelium and initiate clotting in the subendothelium). This hypothesis will be examined in cell culture and animal models. Because our previous work has shown that augmentation of EC cGMP suppresses H-induced binding of leukocytes, the ability of maneuvers which elevate intracellular cGMP levels to block P-selectin expression will be studied as a potentially protective therapeutic intervention. The second aim is to study H-mediated induction of Interleukin 6 (IL-6) a cytokine with anti-inflammatory and neuroprotective properties, which may promote cellular survival during oxygen deprivation. These experiments will examine molecular mechanisms underlying enhanced expression of Il-6 in H at the promoter level, based on our recent finding that the NF-IL-6 promoter has a central role in gene expression under H. We will also address the potential protective effects of il-6 in models of pulmonary and cerebral ischemia using wild-type and deletionally mutant Il-6 transgenic mice. Work in project V will be carried out closely with studies proposed in other parts of the PERC: (i) we will assist in experiments to determine mechanisms underlying the H-induced increase in corticotropin-releasing hormone expression in the placenta (Goland); and (ii) we will participate int he sheep (Dr. Daniel) and baboon models (Dr. Stark) of placental ischemia to determine if mechanisms identified in our studies are operative in these settings relevant to perinatology. Through a combination of in vitro and in vivo studies, involving Project V and its interactions with the other projects in the PERC, we seek to accomplish the long-term objective of understanding how the response to H perturbs cellular functions and brings about adaptations critical to survival during oxygen deprivation.