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。 针对慢性亚致死性低氧，初步研究 表现出显著的皮质血管生成和通透性 改变。尽管这种反应被认为可以改善新陈代谢 在皮质生成的关键时期的供应，机制 它的潜在原因很大程度上是未知的，因为它的长期后果是 这种微血管反应。 Beagle脑微血管内皮细胞的三维培养 (BBMEC)/新生大鼠星形胶质细胞共培养为 发育中的脑微血管的研究。这个系统 论证了血脑发育的特点 体外屏障，并进行积极的血管生成反应 慢性亚致死性低氧应激。我们假设这个系统 将为生长因子介导的神经胶质细胞的研究提供模型 慢性亚致死性血管内皮细胞信号转导 缺氧侮辱。先前的经验表明，血管 血管内皮细胞生长因子，转化生长因子-β (转化生长因子-β)和成纤维细胞生长因子对此至关重要。 我们的研究将针对这三个增长因素。我们 也将检验这样一种假设，即这些增长因素被发现是 对体外低氧诱导血管生成的关键作用 不仅介导低氧诱导血管生成，而且还介导血管生成 体内发现微血管通透性的变化。除了……之外 对在慢性亚致死性缺氧中饲养的动物的研究，我们将 稳定表达这些生长的成纤维细胞 因子进入新生大鼠的大脑皮层以刺激我们的模型 慢性亚致死性缺氧。最后，使用新生大鼠模型，我们 将检验这样一种假设，即那些被识别为 在体外发育和缺氧方面的差异调节将 也在体内低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.