Dynamic Single Cell Imaging of Coronary Microvascular Dysfunction in the Failing Heart

心力衰竭冠状动脉微血管功能障碍的动态单细胞成像

• 批准号: 10523513
• 负责人: Aaron D Aguirre
• 金额: $ 41.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523513
• 关键词: Acute myocardial infarction; Adenosine; Affect; Animal Model; Arteries; Atherosclerosis; Blood Vessels; Blood capillaries; Blood flow; Brain; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Clinical; Clinical Treatment; Complex; Computer Models; Coronary; Coronary Arteriosclerosis; Coronary Vessels; Coronary artery; Coronary heart disease; Diagnosis; Diameter; Epidemic; Erythrocytes; Exercise; Exhibits; Fibrosis; Flow Cytometry; Four-dimensional; Functional disorder; Future; Heart; Heart Diseases; Heart Injuries; Heart failure; Heterogeneity; Histologic; Hyperemia; Hypertrophy; Image; Image Cytometry; In Vitro; Individual; Inflammation; Inflammatory Response; Link; Maps; Measures; Membrane Potentials; Metabolic; Metabolism; Methods; Microcirculation; Microscopy; Microvascular Dysfunction; Modeling; Molecular; Morphologic artifacts; Motion; Mus; Muscle Cells; Myocardial; Myocardial Ischemia; NADH; Neurosciences; Optics; Organ; Pathologic; Pathology; Patients; Pattern; Pericytes; Physiological; Physiology; Property; Protocols documentation; Regulation; Reporter; Resistance; Resolution; Role; Science; Stress; Techniques; Testing; Therapeutic; Time; Transgenic Mice; Tumor Biology; Veins; Work; aging population; aorta constriction; automated image analysis; cellular imaging; clinical diagnosis; empowerment; experimental study; heart imaging; hemodynamics; high resolution imaging; imaging modality; improved; in vivo; innovation; insight; intravital imaging; intravital microscopy; mouse model; novel strategies; novel therapeutics; optogenetics; pharmacologic; physiologic model; pressure; quantitative imaging; response; therapeutic development; tool; two photon microscopy

Despite decades of advances in clinical diagnosis and treatment of heart disease, there is a rising epidemic of heart failure in an aging population worldwide. Historically, much focus has been on atherosclerosis, acute myocardial infarction, and treatment of large vessel coronary disease. However, relatively little is known at a mechanistic level about the vast network of small arteries, capillaries and veins in the heart beyond the large coronary arteries, the coronary microcirculation, and increasing evidence links dysfunction of the microcirculation to various forms of heart disease including heart failure. In vitro experiments, histologic analysis, and computational modeling have provided insight about how the coronary microcirculation is regulated and remodels in the failing heart, but prior studies have been unable to directly evaluate the complex microcirculatory physiology of the heart at the cellular level in vivo. Intravital optical microscopy is being used in the neurosciences and tumor biology to decipher dynamic vascular physiology in vivo, but these techniques have not been applicable in the heart due to severe imaging limitations imposed by contractile motion. We have recently pioneered intravital imaging methods to perform motion-artifact free, cellular resolution microscopy in the beating heart. Building on this work, this proposal seeks to investigate mechanisms of coronary microvascular dysfunction by utilizing intravital microscopy to quantitatively map flow in the coronary microcirculation down to the capillary level in animal models of heart disease. Studies will be performed in mice comparing microcirculatory function in healthy controls, in a model of physiologic hypertrophy due to exercise, and in a model of pressure overload leading to pathologic hypertrophy and heart failure. In addition, the specific role of microvascular pericytes will be investigated as a master regulator of capillary blood flow. Intravital confocal and two-photon microscopy, multiplexed fluorescent reporters, and cell-specific optogenetics approaches will be used to record and manipulate microvascular flow, and to correlate abnormal flow patterns with cardiomyocyte metabolism, inflammatory response, and fibrosis. This work will lead to new understanding of microcirculatory pathophysiology in the failing heart at the single cell level and promising new insights for clinical therapeutics.

尽管在心脏病的临床诊断和治疗方面有数十年的进步，但仍有上升的流行病 全世界人口老龄化的心力衰竭。从历史上看，很大的重点是动脉粥样硬化，急性 心肌梗塞和大血管冠状动脉疾病的治疗。但是，在 关于大型小动脉，毛细血管和静脉的巨大网络的机械水平 冠状动脉，冠状动脉微循环和越来越多的证据 微循环到各种形式的心脏病，包括心力衰竭。在体外实验，组织学 分析和计算建模提供了有关冠状动脉微循环的见解 在失败的心脏中受到调节和改造，但是先前的研究无法直接评估复合物 体内细胞水平的心脏的微循环生理。插入性光学显微镜被用于 神经科学和肿瘤生物学在体内破译动态血管生理学，但是这些技术 由于收缩运动施加的严重成像限制，因此不适用于心脏。我们 最近有开创性的静脉成像方法，以执行无运动艺术的无运动，细胞分辨率 在跳动心脏中的显微镜。在这项工作的基础上，该提议旨在调查 冠状动脉微血管功能障碍通过使用浸润学显微镜在冠状动脉中定量地图 在心脏病动物模型中，微循环至毛细血管水平。研究将在小鼠中进行 比较健康对照中的微循环功能，在锻炼的生理肥大模型中 在压力超负荷的模型中导致病理肥大和心力衰竭。另外， 微血管周细胞的特定作用将作为毛细血管血流的主要调节剂进行研究。 插入式共聚焦和两光子显微镜，多路复用的荧光记者以及细胞特异性光遗传学 方法将用于记录和操纵微血管流，并与异常流动模式相关 与心肌细胞的代谢，炎症反应和纤维化。这项工作将带来新的理解 单细胞水平失败心脏中的微循环病理生理学，并有希望的新见解 临床疗法。

项目成果

Intravital Microscopy in Atherosclerosis Research.

• DOI: 10.1007/978-1-0716-1924-7_40
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)

The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages.

• DOI: 10.1126/sciimmunol.aaz1974
• 发表时间: 2020-09-25
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Calcagno DM;Ng RP Jr;Toomu A;Zhang C;Huang K;Aguirre AD;Weissleder R;Daniels LB;Fu Z;King KR
• 通讯作者: King KR

Optical Coherence Tomography of Plaque Vulnerability and Rupture: JACC Focus Seminar Part 1/3.

• DOI: 10.1016/j.jacc.2021.06.050
• 发表时间: 2021-09-21
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: Aguirre, Aaron D.;Arbab-Zadeh, Armin;Soeda, Tsunenari;Fuster, Valentin;Jang, Ik-Kyung
• 通讯作者: Jang, Ik-Kyung