CELLULAR AND MOLECULAR BASIS OF ANGIOGENESIS IN DEVELOPING BRAIN

在发育中的大脑中，大脑微血管表现出可塑性。 针对慢性亚致死性缺氧，初步研究 显示出显著的皮质血管生成和渗透性 变化 尽管这种反应被认为可以改善代谢 在皮质生成的关键时期供应， 它的潜在原因在很大程度上是未知的， 这种微血管反应。 Beagle犬脑微血管内皮细胞的三维模型 （BBMEC）/新生大鼠星形胶质细胞共培养为研究脑胶质细胞的分化提供了良好的模型。 脑微血管发育的研究。 该系统 展示了血脑特征的发展 在体外的屏障，并经历积极的血管生成， 慢性亚致死低氧应激 我们假设这个系统 将为研究生长因子介导的胶质细胞增生提供模型 慢性亚致死性心肌炎继发的内皮信号传导 缺氧损伤。 以往的经验表明， 内皮生长因子（VEGF），转化生长因子-β （TGF-β）和成纤维细胞生长因子（FGF）对此至关重要 我们的研究将针对这三个增长因素。 我们 还将检验这些生长因子被发现是 在体外低氧诱导血管生成的关键将 不仅介导缺氧诱导血管生成， 在体内发现的微血管通透性的变化。 除了 研究动物饲养在慢性亚致死缺氧，我们将 用表达这些生长因子稳定转染的植入成纤维细胞 因子进入新生大鼠的皮层，以刺激我们的模型， 慢性亚致死性缺氧 最后，利用新生大鼠模型，我们 将检验一个假设， 在体外发育和缺氧中的差异调节将 也在体内缺氧诱导血管生成中发挥作用。

In the developing brain, the cerebral microvessels exhibit plasticity. In response to chronic sublethal hypoxia, preliminary studies demonstrate significant cortical angiogenesis and permeability changes. Although this response is believed to improve metabolic supply during critical periods of corticogenesis, the mechanisms underlying it are largely unknown as are the long-term consequences of this microvascular response. The three-dimensional beagle brain microvascular endothelial cells (BBMEC)/neonatal rat astrocyte coculture provides a good model for the study of the developing cerebral microvasculature. This system demonstrates the development of the characteristics of the blood-brain barrier in vitro and undergoes active angiogenesis in response to chronic sublethal hypoxia stress. We hypothesize that this system will provide a model for the study of growth factor mediated glial endothelial signaling which occurs secondary to chronic sublethal hypoxia insult. Previous experience suggests that vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta) and fibroblast growth factor (FGF) are critical to this response, and our studies will target these three growth factors. We will also test the hypothesis that those growth factors found to be critical for the hypoxic induction of angiogenesis in vitro will mediate not only the hypoxic induction of angiogenesis but also the changes in microvascular permeability found in vivo. In addition to studies of animals reared in chronic sublethal hypoxia, we will implant fibroblasts stably transfected with an expressing these growth factors into the cortex of neonatal rats to stimulate our model of chronic sublethal hypoxia. Finally, using the neonatal rat model, we will test the hypothesis that those genes identified as being differentially regulated in both development and hypoxia in vitro will also play a role in the hypoxic induction of angiogenesis in vivo.