Regulation of vascular maturation/regression in diabetes

糖尿病血管成熟/退化的调节

• 批准号: 7992095
• 负责人: JIAN-XIONG CHEN
• 金额: $ 38.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992095
• 关键词: Abbreviations; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Apoptosis; Attenuated; Blood Vessels; Blood capillaries; Cardiovascular system; Characteristics; Coculture Techniques; Coronary; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Endothelial Cells; G-Protein-Coupled Receptors; Glucose; Goals; Growth; Heart; Hyperglycemia; Hypoxia; Hypoxia Inducible Factor; Impairment; Knock-out; Laboratories; Lead; Ligands; Link; Mediating; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Oxygen; Pathway interactions; Phosphorylation; Procollagen-Proline Dioxygenase; Production; Receptor Protein-Tyrosine Kinases; Regulation; Role; Signal Transduction; Smooth Muscle Myocytes; System; Testing; Time; Up-Regulation; Vascular Endothelial Growth Factors; angiogenesis; base; capillary; db/db mouse; density; diabetic; diabetic patient; improved; in vivo Model; inhibitor/antagonist; mortality; mouse model; novel; novel therapeutics; overexpression; prevent; public health relevance; sensor; therapeutic target; treatment strategy; vessel regression

DESCRIPTION (provided by applicant): Impairment of myocardial angiogenesis and coronary collateral growth may contribute to high mortality in diabetic myocardial infarction. Our long-term goal is to define the molecular mechanism(s) responsible for abnormal vascular maturation and impairment of angiogenesis in the diabetic hearts. This revised proposal will investigate a possible disruption in the angiopoietins (Ang)/Tie-2 and apelin pathway in abnormal diabetes- associated vascular maturation and capillary regression. Our laboratory has shown a sustained increase in angiopoietin-2 (Ang-2) and prolyl hydroxylase-2 (PHD2) expression, and reduced Ang-1/Tie-2 and HIF- 11/apelin expression in diabetic mice. Our previous demonstration of impaired myocardial vessel maturation in diabetic mice; implicate that disruption of angiopoietins/Tie-2 system in favor of Ang-2, which leading to immature vessel formation and capillary regression, might be a novel mechanism responsible for impaired angiogenesis in diabetic hearts. Our overall hypothesis is that diabetes disrupts Ang-1/Tie-2 and apelin pathway by a mechanism involving Ang-2 and PHD2 activation; and these abnormalities lead to abnormal vascular maturation and capillary regression in diabetic hearts. Specific Aim 1 will define the mechanism(s) by which hyperglycemia interferes with vascular maturation and capillary regression with a focus on the role of Ang-2 in the disruption of Ang-1/Tie-2 and apelin pathway. Using heart microvascular endothelial cells (EC), co-cultured EC-SMC spheroids and mouse aortic explants isolated from wild type (WT) or diabetic db/db mice, we will determine whether: (i) high glucose-induced excess of Ang-2 disrupts Ang-1/Tie-2 signaling and attenuates Ang-1-induced apelin expression; and (ii) interactions between Ang-2 and apelin are critical for the regulation of angiogenesis and vascular regression under high glucose conditions. In specific aim 2, we will determine the role of Ang-2 and PHD2 activation in diabetes-associated disruption of vascular maturation and angiogenesis and promotion of vessel regression in an in vivo model of myocardial ischemia. Using Ang-2 deficient and PHD2 conditional knockout diabetic mice models, we will determine whether deficiency of Ang-2 or endothelial cell deletion of PHD2 rescues impaired apelin expression, normalizes immature neovessels, and improves myocardial angiogenesis. In specific aim 3, we will further determine whether systemic administration of apelin rescues impaired angiogenic signaling, normalizes immature neovessels, and increases myocardial angiogenesis in diabetic hearts. Our studies will provide a framework for the development of a targeted therapeutic reduction in Ang-2 and PHD2 activation to ameliorate or reverse the abnormalities in diabetic vessel maturation and angiogenesis that characterizes the diabetic state. PUBLIC HEALTH RELEVANCE: Impairment of myocardial angiogenesis and coronary collateral growth has contributed to high mortality in diabetic patients. The long-term objectives of this proposal are to explore the molecular mechanisms and novel pathways of hyperglycemia-induced disruption of the angiopoietins/Tie-2 and apelin/APJ interaction that contributes to the abnormal myocardial vasculature maturation and angiogenesis in diabetes. Our proposed studies should provide a framework for developing new therapeutic strategies for the treatment of diabetic impaired collateralization and angiogenesis.

描述（由申请人提供）：心肌血管生成和冠状动脉附带生长的损害可能导致糖尿病心肌梗死的高死亡率。我们的长期目标是定义糖尿病心脏中血管生成异常的血管成熟和损害的分子机制。这项修订后的建议将研究异常糖尿病相关的血管成熟和毛细血管回归中血管生成素（ANG）/TIE-2和APELIN途径的可能中断。我们的实验室表明，在糖尿病小鼠中，血管生成素2（ANG-2）和羟基羟化酶-2（PHD2）表达的持续增加，ANG-1/TIE-2和HIF-11/APELIN表达降低。我们以前在糖尿病小鼠中表明心肌血管成熟受损的证明；暗示了血管生成蛋白/TIE-2系统的破坏而有利于ANG-2，从而导致不成熟的血管形成和毛细管回归，这可能是导致糖尿病心脏血管生成受损的新机制。我们的总体假设是，糖尿病通过涉及ANG-2和PHD2激活的机制破坏ANG-1/TIE-2和APELIN途径。这些异常导致糖尿病心脏中的血管成熟和毛细血管回归异常。特定的目标1将定义高血糖会干扰血管成熟和毛细管回归的机制，重点是ANG-2在ANG-1/TIE-2和Apelin途径破坏中的作用。使用心脏微血管内皮细胞（EC），共培养的EC-SMC球体和从野生型（WT）或糖尿病DB/DB小鼠中分离出来的小鼠主动脉植物，我们将确定：（i）高葡萄糖是否会高葡萄糖诱导的Ang-2 Ang-1 Ang-1/Tie-2信号传递和actentens Ang-1 Ang-1 Ang-1 Ang-1 Ang-1-Ang-1 Angene Ang-1-Ang-1诱发的APELINS APELINS APELINS APELINS APELINS APELINS APELINS APELINS APELINS CALIN蛋白表达； （ii）Ang-2和Apelin之间的相互作用对于在高葡萄糖条件下的血管生成和血管回归的调节至关重要。在特定的目标2中，我们将确定ANG-2和PHD2激活在与糖尿病相关的血管成熟和血管生成的破坏中的作用，并在心肌缺血的体内模型中血管回归的作用。使用ANG-2缺乏和PHD2有条件敲除糖尿病小鼠模型，我们将确定ANG-2的缺乏或PHD2的内皮细胞缺失是否会挽救Apelin表达受损，使未成熟的NEOVESSELS归一化，并改善心肌血管生成。在特定的目标3中，我们将进一步确定Apelin的全身施用是否会损害血管生成信号传导，使未成熟的新系列归一化，并增加糖尿病心脏中心肌血管生成。我们的研究将为开发ANG-2和PHD2激活的靶向治疗降低提供一个框架，以改善或逆转糖尿病血管成熟和血管生成的异常，以表征糖尿病状态。 公共卫生相关性：心肌血管生成和冠状动脉附带增长的损害导致糖尿病患者的死亡率高。该提案的长期目标是探索高血糖诱导的血管生成素/TIE-2和APELIN/APJ相互作用的分子机制和新的途径，这些破坏有助于心肌内部心肌血管成熟和血管生成。我们提出的研究应为开发新的治疗策略提供一个框架，以治疗糖尿病受损的抵押和血管生成。