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.

项目总结/摘要 胸主动脉瘤是一种疾病过程，其涉及由其血管壁的弱化引起的血管扩张。 墙这种主动脉的扩张有可能导致破裂和死亡，除非采取戏剧性的治疗。 外科手术置换患病的主动脉。手术适应症主要取决于大小， 抓住所有有破裂和死亡风险的人虽然已经提出了各种理论，但分子 并且还没有阐明主动脉壁弱化的生物力学原因。因此，新的疗法， 预防或逆转这种疾病的过程尚未产生。 主动脉壁由三层组成，分别为内膜、中膜和外膜。在主动脉瘤，光滑 肌细胞死亡和弹性蛋白纤维断裂是典型的观察过程中，称为囊性内侧 退化虽然许多研究以前都集中在主动脉媒体，最近的工作已经把重点放在 在主动脉的外层主动脉外膜包含许多称为血管的小血管 提供血液流向主动脉壁外半部的血管。血管是由 内皮细胞和支持性周细胞调节通过这些血管的流动。我们实验室最近的一项研究 已经揭示了动脉瘤人类主动脉中的血管缺陷和功能失调。外半部分缺氧 还观察到与血管形成相关的生长因子减少。基于 基于这一认识，我们认为血管功能障碍引起的灌注减少会导致缺氧， 随后主动脉壁变弱。本研究的目的是在周细胞水平上研究这种疾病的过程 支撑着血管初步研究结果显示，人类主动脉瓣闭锁衍生的 参与血管的形成和成熟的周细胞功能失调。此外，细胞外 来自人平滑肌主动脉组织的基质（ECM）对正常主动脉周细胞产生有害作用， 内皮细胞鉴于这些发现，我们假设主动脉瘤是由细胞功能障碍引起的。 和有助于血管形成的细胞外基质。 具体目的1：比较血管周细胞和人血管外膜ECM的功能， 正常主动脉组织 具体目标2：研究猪ECM在兔动脉瘤模型中的治疗应用 通过这项研究，我们试图确定新的治疗生物材料，如猪细胞外， 基质水凝胶。我们这个项目的长期目标是提高对主动脉夹层风险的识别 或破裂，并提供预防胸主动脉疾病后遗症的微创治疗方式。