Pericyte and Extracellular Matrix Dysfunction in Thoracic Aortic Aneurysm

胸主动脉瘤的周细胞和细胞外基质功能障碍

• 批准号: 10536464
• 负责人: Bryant Fisher
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536464
• 关键词: 3-Dimensional; Address; Aneurysm; Animal Model; Aorta; Aortic Aneurysm; Aortic Diseases; Biocompatible Materials; Biomechanics; Blood Vessels; Blood flow; Calcium Chloride; Cell Death; Cessation of life; Chest; Clinical; Complex; Dilatation - action; Disease; Dissection; Elastases; Elastin Fiber; Endothelial Cells; Exhibits; Extracellular Matrix; Family suidae; Fibroblast Growth Factor; Functional disorder; Goals; Growth Factor; Histologic; Human; Hydrogels; Hypoxia; Impairment; In Vitro; Interruption; Knowledge; Lead; Medial; Modality; Modeling; Molecular; Morbidity - disease rate; Operative Surgical Procedures; Oryctolagus cuniculus; Pathogenesis; Pathway interactions; Perfusion; Pericytes; Pharmacology; Process; Property; Research; Risk; Rupture; Smooth Muscle Myocytes; Therapeutic; Therapeutic Effect; Thoracic Aortic Aneurysm; Tissues; Transforming Growth Factor beta; Tunica Adventitia; Vascular Endothelial Growth Factors; Work; angiogenesis; base; blood vessel development; improved; improved functioning; in vivo; inhibitor; intima media; mortality; new therapeutic target; novel therapeutics; patient population; platelet-derived growth factor BB; prevent; regeneration potential; regenerative; regenerative therapy; screening; theories; vasa vasorum

Project Summary/Abstract A thoracic aortic aneurysm is a disease process that involves dilation of the vessel caused by a weakening of its wall. This dilation of the aorta has the potential to lead to rupture and death unless treated with a dramatic surgical intervention to replace the diseased aorta. Indications for surgery largely rely on size and often fail to capture all of those at risk for rupture and death. While various theories have been put forward, the molecular and biomechanical causes of aortic wall weakening have not been elucidated. Consequently, novel therapies to prevent or reverse this disease process have not been produced. The aortic wall consists of three layers identified as the intima, media, and adventitia. In aortic aneurysm, smooth muscle cell death and elastin fiber fragmentation is typically observed in a process termed cystic medial degeneration. While many studies have previously focused on the aortic media, recent work has placed focus on the outer layer of the aorta. The aortic adventitia contains numerous small blood vessels known as vasa vasorum which provide blood flow to the outer half of the aortic wall. The vasa vasorum are made up of endothelial cells and supportive pericytes which regulate flow through these vessels. A recent study in our lab has revealed deficient and dysfunctional vasa vasorum in aneurysmal human aorta. Hypoxia in the outer half of the aorta and a decrease in growth factors associated with blood vessel formation were also observed. Based on this knowledge, we posit that a reduction in perfusion from vasa vasorum dysfunction leads to hypoxia and subsequent aortic wall weakening. This study aims to examine this disease process at the level of the pericytes which support the vasa vasorum. Preliminary findings have revealed that human aortic aneurysm-derived pericytes involved in the formation and maturation of vasa vasorum are dysfunctional. In addition, extracellular matrix (ECM) from human aneurysmal aortic tissue produces deleterious effects on normal aortic pericytes and endothelial cells. Given these findings, we hypothesize that aortic aneurysm arises from dysfunction in the cells and extracellular matrix that contribute to vasa vasorum formation. Specific Aim 1: Compare function of vasa vasorum pericytes and human adventitial ECM from aneurysmal and normal aortic tissue Specific Aim 2: Investigate therapeutic applications of porcine ECM in rabbit aneurysm model Through this study, we seek to identify targets for novel therapeutic biomaterials such as porcine extracellular matrix hydrogel. Our long-term goal of this project is to improve identification of those at risk for aortic dissection or rupture and to provide less-invasive treatment modalities that prevent the sequelae of thoracic aortic disease.

项目摘要/摘要 胸动脉瘤是一种疾病过程，涉及由于其减弱的血管扩张 墙。这种主动脉的扩张有可能导致破裂和死亡，除非用戏剧性治疗 手术干预以取代患病主动脉。手术的适应症很大程度上依赖于大小，并且常常无法 捕获所有有破裂和死亡风险的人。虽然提出了各种理论，但分子 主动脉壁弱化的生物力学原因尚未阐明。因此，新颖的疗法 尚未产生预防或扭转这种疾病过程。 主动脉墙由三层层组成，被称为内膜，媒体和外膜。在主动脉动脉瘤中，光滑 通常在称为囊性内侧的过程中观察到肌肉细胞死亡和弹性蛋白纤维碎裂 退化。尽管许多研究以前都专注于主动脉介质，但最近的工作将重点放在了重点 在主动脉的外层。主动脉膜中包含许多称为VASA的小血管 流动流向主动脉壁的外半部的血管。 Vasa Vasorum由 内皮细胞和支撑性周细胞，这些细胞调节这些血管的流动。我们实验室的最新研究 揭示了动脉瘤人主动脉瘤中缺乏和功能失调的VASA血管。缺氧 还观察到主动脉和与血管形成相关的生长因子的减少。基于 因此，我们认为从Vasa vasorum功能障碍减少灌注会导致缺氧和 随后的主动脉壁减弱。这项研究旨在检查周细胞水平的这种疾病过程 支持Vasa vasorum。初步发现表明人类主动脉瘤衍生 与瓦萨·巴萨鲁姆（Vasa Batorum）形成和成熟有关的周细胞功能失调。另外，细胞外 人动脉瘤主动脉组织的基质（ECM）对正常主动脉周细胞产生有害影响 内皮细胞。鉴于这些发现，我们假设主动脉瘤来自细胞中的功能障碍 和细胞外基质有助于瓦萨·瓦萨形成。 特定目的1：比较脉管周周的功能和来自动脉瘤的人类外在ECM的功能 正常主动脉组织 特定目标2：研究猪ECM在兔动脉瘤模型中的治疗应用 通过这项研究，我们试图确定新型治疗性生物材料（例如猪外细胞外）的靶标 基质水凝胶。该项目的长期目标是改善对主动脉剖析风险的人的识别 或破裂并提供较少侵入性的治疗方式，以防止胸腔主动脉疾病的后遗症。