Oct4 and Klf4 regulate microvascular SMC-pericyte plasticity, angiogenesis, and metabolic dysfunction

Oct4 和 Klf4 调节微血管 SMC-周细胞可塑性、血管生成和代谢功能障碍

• 批准号: 9919376
• 负责人: Gary K Owens
• 金额: $ 76.9万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919376
• 关键词: Address; Adipocytes; Adipose tissue; Area; Atherosclerosis; Attenuated; B-Lymphocytes; Binding; Blindness; Blood; Blood Vessels; CD14 gene; Cells; Characteristics; Clinical; Clinical Trials; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diet; Disease; Elements; Endothelial Cells; Enhancers; Epigenetic Process; Exhibits; Failure; Frequencies; Functional disorder; Genes; Genomics; Grant; HIF1A gene; Heart failure; Homeostasis; Human; Hyperglycemia; Hypoxia; Impairment; Individual; Inflammation; Inflammatory; Investments; Kidney Failure; Knock-out; Knowledge; Lead; Macular degeneration; Mediating; Mesentery; Metabolic; Metabolic Diseases; Metabolic dysfunction; Methods; Microcirculatory Bed; Microscopic; Microvascular Dysfunction; Microvascular Permeability; Modeling; Mus; Mutation; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity Epidemic; Oxygen; Pathogenesis; Patients; Pericytes; Phenotype; Play; Population; Process; Property; Recovery; Reporter; Role; Smooth Muscle Myocytes; Stroke; Structure; T-Lymphocyte; Testing; Thinness; Tissue Sample; Tissues; Transgenic Mice; Tube; Vascular Endothelial Growth Factors; Vascular remodeling; Vascularization; angiogenesis; base; cell motility; cell type; conditional knockout; corneal burn; human tissue; improved; in vivo; injury and repair; ischemic injury; limb ischemia; macrophage; macula; novel therapeutic intervention; pluripotency; prevent; promoter; protective effect; recruit; response to injury; skin wound; stem cells; therapeutic angiogenesis; tissue injury; transcriptome sequencing; virtual; wound healing; wound response

Microvascular inflammation and dysfunction is widely believed to be the underlying cause of many of the clinical complications of diabetes and metabolic disease including renal and heart failure, neuropathy, and maculae degeneration. Much is known regarding mechanisms by which leucocytes and endothelial cells (EC) contribute to this process. However, in spite of compelling evidence that abnormal investment of perivascular smooth muscle cells and pericytes (SMC-Pc) is a common feature of microvascular disease pathogenesis, little is known regarding the role or mechanisms by which these cells might contribute to this process. Inadequate SMC-Pc investment of nascent EC tubes is also a major rate-limiting factor in attempts to induce therapeutic angiogenesis to augment wound repair or recovery from ischemic injury. Indeed, this includes many failed VEGF clinical trials where there is robust formation of EC tubes but failure to form a mature functional vascular network with efficient blood delivery because vessels lack SMC-Pc coverage and are dilated and leaky. Studies in this proposal will test the overall hypothesis that the stem cell pluripotency genes Oct4 and Klf4 play a critical role in regulating the plasticity of microvascular SMC-Pc during vascular remodeling in response to injury and hypoxia, as well as development of microvascular inflammation and dysfunction associated with metabolic disease. Consistent with this hypothesis, initial studies by our lab using unique SMC-Pc specific eYFP lineage tracing mice +/- simultaneous conditional knockout (KO) of Oct4 exclusively in SMC-Pc showed that Oct4 expression within SMC-Pc is required for functional angiogenesis in corneal burn and hind limb ischemia models. Moreover, we present exciting new data in this revised application showing that Klf4 expression within microvascular SMC-Pc plays a critical role in regulating the innate metabolic and inflammatory properties of the mesenteric microvascular network and surrounding adipose tissue even in non-hyperlipidemic mice. Aim 1 will test the hypothesis that activation of Oct4 within microvascular SMC-Pc is a key rate-limiting step in both normal and dysfunctional angiogenesis including that associated with diet-induced obesity (DIO)/metabolic disease. Aim 2 will determine mechanisms that regulate Oct4 re-activation within microvascular SMC-Pc including testing the hypothesis that it is hypoxia, NFκB, and Klf4-dependent. Aim 3 will test the hypothesis that Klf4-dependent phenotypic transitions of microvascular SMC-Pc play a key protective role in regulating the innate metabolic and inflammatory properties of normal adipose tissue and that loss of these protective effects contribute to global microvascular inflammation/dysfunction during development of metabolic disease. Studies may lead to novel therapeutic approaches for enhancing therapeutic angiogenesis and/or treating and preventing microvascular disease complications of diabetes and metabolic disease.

微血管炎症和功能障碍被广泛认为是许多临床疾病的根本原因。 糖尿病和代谢性疾病的并发症，包括肾衰竭和心力衰竭、神经病变和黄斑 退化关于白细胞和内皮细胞（EC）参与的机制已经知道很多。 这个过程。然而，尽管有令人信服的证据表明，异常投资的血管周围光滑 肌细胞和周细胞（SMC-Pc）是微血管病发病机制的共同特征，目前知之甚少 关于这些细胞可能有助于这一过程的作用或机制。SMC-Pc不足 新生EC管的投资也是试图诱导治疗性血管生成的主要限速因素 以增强伤口修复或从缺血性损伤中恢复。事实上，这包括许多失败的VEGF临床试验， 其中存在EC管的稳健形成，但未能形成具有有效的功能的成熟的功能性血管网络， 因为血管缺乏SMC-Pc覆盖并且扩张和渗漏。本提案中的研究将 测试干细胞多能性基因Oct 4和Klf 4在以下方面发挥关键作用的总体假设： 调节微血管SMC-Pc的可塑性，在血管重塑过程中对损伤的反应， 缺氧，以及微血管炎症和功能障碍的发展， 代谢性疾病与这一假设一致，我们实验室使用独特的SMC-Pc特异性 eYFP谱系追踪小鼠+/-同时条件性敲除（KO）仅在SMC-Pc中敲除Oct 4，显示 SMC-Pc中Oct 4表达是角膜烧伤和后肢功能性血管生成所必需的， 缺血模型。此外，我们在这个修订后的应用程序中提供了令人兴奋的新数据，表明Klf 4 在微血管SMC-Pc中的表达在调节先天代谢和炎症反应中起着关键作用。 肠系膜微血管网和周围脂肪组织的性质，即使在非高血压 小鼠目的1将检验微血管SMC-Pc中Oct 4的激活是一个关键的限速因素的假设。 正常和功能失调血管生成中的步骤，包括与饮食诱导的肥胖相关的步骤 (DIO)/代谢性疾病。目的2将确定调节微血管内Oct 4再激活的机制， SMC-Pc包括检验其为缺氧、NFκB和Klf 4依赖性的假设。目标3将测试 微血管SMC-Pc的Klf 4依赖性表型转变在 调节正常脂肪组织的固有代谢和炎症特性， 保护作用有助于代谢性疾病发展过程中的整体微血管炎症/功能障碍 疾病研究可能导致用于增强治疗性血管生成和/或治疗和/或预防的新的治疗方法。 预防糖尿病和代谢性疾病的微血管疾病并发症。