Mechanisms of ER71/ETV2-regulated Vascularization

ER71/ETV2 调节血管化的机制

• 批准号: 10215598
• 负责人: Changwon Park
• 金额: $ 36.5万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215598
• 关键词: Address; Adult; Age related macular degeneration; Anti-Inflammatory Agents; Beginning of Life; Binding; Biological; Biological Assay; Biology; Blood Vessels; Blood flow; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Line; Cells; ChIP-seq; Chromatin; Comprehension; Development; Disease; ETS Family Protein; Endothelial Cells; Endothelium; Enhancers; Epigenetic Process; Exhibits; Eye Injuries; Family; Fetus; Foundations; Gene Expression; Gene Expression Profiling; Generations; Genes; Genetic Transcription; Goals; Hindlimb; Impairment; Inflammation; Injury; Intervention; Investigation; Ischemia; KDR gene; Knockout Mice; Knowledge; Lasers; Lead; Lesion; Life; LoxP-flanked allele; Luciferases; Maintenance; Mediating; Methylation; Modeling; Molecular; Molecular and Cellular Biology; Morbidity - disease rate; Mus; Natural regeneration; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral arterial disease; Physiology; Play; Property; Public Health; Recovery; Regulation; Reporting; Rest; Role; Signal Transduction; Solid; System; Systems Development; Testing; United States; Vascular Endothelial Cell; Vascular System; Vascularization; Work; XCL1 gene; base; chromatin immunoprecipitation; conditional knockout; design; epigenetic regulation; experimental study; histone demethylase; histone methylation; improved; injury recovery; innovation; insight; ischemic injury; member; mortality; mouse genetics; mouse model; neovascularization; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; postnatal; progenitor; promoter; repaired; response; skin wound; therapeutically effective; therapy development; tissue injury; tissue repair; tool; transcription factor; tumor; wound healing

Abstract Our understanding on the cardiovascular system has been widened over the past decades, but still millions of patients with cardiovascular disease (CVD), the most devastating disease in the United States and the rest of the world, await more effective means to treat the disease. Thus, a comprehensive insight into the mechanisms regulating the function of the cardiovascular system is urgently needed. Previously, we have demonstrated an indispensable role of the transcription factor ETV2 (also known as ER71) in cardiovascular system development. Also, our recent studies with genetically modified mice provide compelling evidence that show ETV2’s potent and novel functions in the vascular regeneration in adults. Mice lacking endothelial ETV2 exhibit significantly impaired new vessel formation in response to tissue injuries including laser-induced eye injury, skin wounding, or hindlimb ischemic injury, which are models for age-related macular degeneration, general wound healing, and peripheral arterial disease, respectively. Moreover, a lentiviral delivery of ETV2 into ischemic hindlimbs leads to an improved recovery of blood flow, augments angiogenic gene expression and enhances vascular regeneration, highlighting a requisite postnatal function of ETV2 in an injury-induced neovascularization. However, current knowledge on mechanisms by which ETV2 functions in the cardiovascular system and vascular regeneration is very limited. Our preliminary results suggest that ETV2 directs the expression of endothelial genes and thus generation of cardiovascular lineages by regulating the status of H3K9 methylation though the interaction with KDM4A, a histone demethylase. In addition, our investigations strongly suggest a functional correlation between the NFB pathway and ETV2 in mediating injury-induced neovascularization. Furthermore, we have several lines of evidence showing that myelomonocyte ETV2 plays a significant role in neovascularization upon ischemic insults. Building upon these strong and novel evidence as well as tools, we will decipher mechanisms and functions of ETV2, 1) by determining the epigenetic regulatory role of the interaction between ETV2 and KDM4A for cardiovascular lineage generation, 2) by investigating the role of the NFB as a direct upstream regulator of ETV2 in mouse models of hindlimb ischemia and tumor, 3) by revealing the novel functions of myelomonocyte ETV2, contributing to neovascularization by regulating inflammation. The outcome of this work will reveal uncovered functions of ETV2 in vascular development and functions as well as tissue repair, significantly advancing our limited knowledge on vascular biology. Thus, our findings could lead to the development of novel, effective therapeutic strategies for diseases related to dysfunctional vessel formation, an important translational aspect of the proposed studies.

抽象的 在过去的几十年中，我们对心血管系统的理解已经扩大，但仍有数百万 心血管疾病（CVD）的患者，美国和其余的疾病最具破坏性的疾病 世界，等待更有效的治疗疾病的方法。那是对 迫切需要应对心血管系统功能的机制。以前，我们有 在心血管中证明了转录因子ETV2（也称为ER71）的必不可少的作用 系统开发。此外，我们最近对一般修改小鼠的研究提供了令人信服的证据 显示了ETV2在成人血管再生中的潜力和新功能。缺乏内皮ETV2的小鼠 响应组织损伤（包括激光引起的眼睛）的新血管形成显着损害了新血管的形成 损伤，皮肤缠绕或后肢缺血性损伤是与年龄相关的黄斑变性的模型 总体伤口愈合和周围动脉疾病。此外，ETV2的慢病毒递送 缺血性后肢导致血流的恢复改善，增强血管生成基因表达 并增强血管再生，突出显示ETV2在损伤引起的 新血管形成。但是，当前关于ETV2在机制中起作用的机制的知识 心血管系统和血管再生非常有限。我们的初步结果表明ETV2 指导内皮基因的表达，从而通过调节心血管谱系的产生 H3K9甲基化的状态通过与Hisstone脱甲基酶KDM4A的相互作用。另外，我们的 研究强烈表明NFB途径与ETV2之间的功能相关性 损伤引起的新血管形成。此外，我们有几条证据表明 脊髓细胞ETV2在缺血性损伤的新血管化中起重要作用。基于这些 强烈而新颖的证据以及工具，我们将破译ETV2的机制和功能，1） 确定心血管中ETV2与KDM4A之间相互作用的表观遗传调节作用 谱系生成2）通过研究NFB作为ETV2的直接上游调节剂的作用 后肢缺血和肿瘤的模型，3）通过揭示骨髓细胞ETV2的新功能， 通过控制炎症来促进新血管化。这项工作的结果将揭示发现 ETV2在血管发育和功能以及组织修复中的功能，显着推进了我们 关于血管生物学的知识有限。这，我们的发现可能导致新颖，有效的发展 与功能失调的血管形成有关的疾病的治疗策略，这是一个重要的翻译方面 拟议的研究。