The Role of ARNT in Endothelial Cells

项目摘要/摘要 缺氧诱导因子(HIF)是组织O2水平的重要感受器，调控血管生成基因 在胚胎发育期间以及在出生后病理中运行的表达程序包括 伤口愈合和缺血。原则上，HIF有助于重要的遗传程序，负责 调节和控制血管生长。缺氧诱导因子缺陷小鼠表现出发育停滞 多发性心血管异常。然而，HIF-规范的特定作用的意义 在血管内皮细胞(ECs)中缺乏信号转导通路。这方面的长期研究目标是 应用于确定HIF如何响应低氧(低氧)环境，调节 维持组织内环境平衡所必需的血管生长。它已经被证明是特定的 HIF的活性依赖于细胞和上下文。这项提议解决了欧共体-- 缺氧诱导因子激活调控血管不同阶段特定类型血管生长的不同基因 发育和出生后血管生成。我们将进一步确定HIF，以应对 低氧可调节血管内皮生长因子受体的瞬时表达，而血管内皮生长因子受体在介导特异性 内皮细胞中的信号包括它们的生存、增殖和行为。实验设计利用了一个 ARNT条件性(血管中HIF必需亚单位)小鼠遗传系统完全失活 胚胎发育不同阶段内皮细胞和成体中HIF转录活性的研究 血管系统使研究低氧诱导因子在内皮细胞中的需求和作用成为可能(S) 血管的建立、成熟和维持，以及对血管损伤的反应。 特定目标1将研究胚胎发育关键阶段内皮细胞中HIF失活如何导致 到特定的血管新生缺陷。目的2探讨成人血管内稳态对缺氧诱导因子的要求(S) 以及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， 目标3将检查内皮细胞内HIF的内在要求，并测试HIF是 重要的是通过调节血管内皮生长因子受体的表达来促进EC的存活。这些研究 旨在扩大我们对低氧调节机制的理解 在正常和病理环境下的血管生成和动态平衡。

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.