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 在过去的几十年里，我们对心血管系统的了解已经扩大，但仍有数百万人 心血管疾病 (CVD) 患者是美国和其他国家最具破坏性的疾病 全世界都在等待更有效的手段来治疗这种疾病，从而全面了解这一疾病。 此前，我们迫切需要调节心血管系统功能的机制。 转录因子ETV2（也称为ER71）在心血管中发挥着不可或缺的作用 此外，我们最近对转基因小鼠的研究提供了令人信服的证据： 显示 ETV2 在缺乏内皮 ETV2 的小鼠血管再生中的强大而新颖的功能。 响应组织损伤（包括激光诱导的眼睛）而表现出明显受损的新血管形成 损伤、皮肤损伤或后肢缺血性损伤，这些都是年龄相关性黄斑变性的模型， 分别为一般愈合伤口和外周动脉疾病。 进入缺血后肢可改善血流恢复，增强血管生成基因表达 并增强血管再生，强调 ETV2 在损伤诱导的产后功能中所必需的 然而，目前关于 ETV2 在血管生成中发挥作用的机制的知识。 我们的初步结果表明ETV2对心血管系统和血管再生的影响非常有限。 通过调节内皮基因的表达，从而指导心血管谱系的产生 H3K9 甲基化状态通过与 KDM4A（一种组蛋白去甲基化酶）相互作用。 研究强烈表明 NFκB 通路和 ETV2 在介导中存在功能相关性 此外，我们有几条证据表明： 骨髓单核细胞 ETV2 在缺血性损伤的新生血管形成中发挥重要作用。 强有力且新颖的证据和工具，我们将破译 ETV2 的机制和功能，1) 确定 ETV2 和 KDM4A 相互作用对心血管的表观遗传调节作用 谱系生成，2) 通过研究 NF+B 作为小鼠 ETV2 直接上游调节因子的作用 后肢缺血和肿瘤模型，3）通过揭示骨髓单核细胞ETV2的新功能， 这项工作的结果将揭示出通过调节炎症来促进新血管形成。 ETV2 在血管发育和功能以及组织修复中的功能，显着推进了我们的研究 因此，我们的研究结果可能会导致新型、有效的药物的开发。 与功能失调的血管形成相关的疾病的治疗策略，这是一个重要的转化方面 拟议的研究。