The Role of ARNT in Endothelial Cells

项目总结/摘要 缺氧诱导因子（Hypoxia Inducible Factor，HIF）是组织氧水平的关键传感器，并控制血管生成基因 在胚胎发生过程中以及在出生后病理学中起作用的表达程序， 伤口愈合和局部缺血。原则上，HIF有助于重要的遗传程序， 调节和控制血管生长。缺乏HIF的小鼠显示发育停滞， 多处心血管异常然而，对于HIF典型的特定作用的意义 血管内皮细胞（EC）中缺乏信号通路。长期的研究目标是 应用是为了确定HIF如何响应缺氧（低氧）环境，调节 维持组织稳态所必需的血管生长。它已经证明了具体的 HIF的活性依赖于细胞和环境。这一建议涉及的一般假设是，欧共体- HIF激活不同的基因，在血管的不同阶段调节特定类型的血管生长。 发育和产后血管生成。我们将进一步确定是否HIF，在响应 缺氧，调节VEGF受体的时间表达，VEGF受体在介导特异性 信号，包括其生存，增殖和行为。实验设计利用了 Arnt条件性（血管中的HIF-ú强制性亚基）小鼠遗传系统完全失活 在胚胎发育的不同阶段以及在成人中的EC中的HIF转录活性 血管系统，使调查HIF的要求（S）和作用（S）在EC期间 血管的建立、成熟和维持以及对血管损伤的反应。 具体目标1将研究胚胎发育关键阶段EC中的HIF失活如何导致 特定的血管生成缺陷。目的2阐述了成人血管稳态对HIF的要求 和各种类型的血管反应（新血管生成、血管生成和动脉生成）。最后， 目的3将检查内皮细胞内HIF的内在要求，并检验HIF是内皮细胞的一部分的假设。 部分通过调节VEGF受体的表达，在促进EC存活中起重要作用。研究 本文提出的旨在扩大我们对缺氧调节的机制的理解， 在正常和病理情况下的血管生成和体内平衡。

Project Summary/Abstract Hypoxia Inducible Factor (HIF) is a critical sensor of tissue O2 levels and governs angiogenic gene expression programs operating during embryogenesis as well as in post-natal pathologies including wound healing and ischemia. In principle, HIF contributes to important genetic programs responsible for moderating and controlling vascular growth. Mice deficient in HIF display developmental arrest due to multiple cardiovascular anomalies. However, the significance of a specific role for the HIF-canonical pathway in vascular endothelial cells (ECs) is lacking. The long-term research objective of this application is to determine how HIF, in response to the hypoxic (low oxygen) environment, regulates vascular growth necessary for maintaining tissue homeostasis. It has been demonstrated the specific activity of HIF is cell- and context- dependent. This proposal addresses the general hypothesis that EC- HIF activates distinct genes regulating specific types of vessel growth at various stages of vascular development and in post-natal angiogenesis. We will further determine whether HIF, in response to hypoxia, moderates the temporal expression of VEGF receptors that are important in mediating specific signals in ECs including their survival, proliferation, and behavior. The experimental design utilizes an Arnt-conditional (HIF-¿ obligatory subunit in vessels) mouse genetic system that completely inactivates HIF-transcriptional activity in ECs at various stages of embryonic development as well as in the adult vasculature enabling the investigations of HIF's requirement(s) and role(s) within ECs during the establishment, maturation, and maintenance of blood vessels as well as in response to vascular injury. Specific Aim 1 will examine how HIF inactivation in ECs at critical stages of embryonic development lead to specific angiogenic defects. Aim 2 addresses the requirement(s) for HIF in adult vessel homeostasis and various types of vascular responses (neoangiogenesis, angiogenesis, and arteriogenesis). Finally, Aim 3 will examine the intrinsic requirements of HIF within ECs and test the hypothesis that HIF is important in promoting EC survival in part by regulating the expression of VEGF receptors. The studies proposed herein intend to expand our understanding of the mechanisms by which hypoxia regulates vessel generation and homeostasis in both normal and pathological settings.