Matrix mediated vasa vasorum dysfunction in thoracic aortic disease

胸主动脉疾病中基质介导的血管滋养功能障碍

• 批准号: 9976570
• 负责人: Julie A Phillippi
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976570
• 关键词: Address; Affect; Aneurysm; Angiogenic Factor; Animal Model; Aorta; Aortic Diseases; Area; Arteries; Award; Biological Models; Biological Response Modifier Therapy; Biology; Biomechanics; Biomimetics; Caliber; Caring; Cell Proliferation; Chest; Chronic; Clinical; Collagen; Collection; Cues; Data; Development; Diagnosis; Diagnostic; Disease; Dissection; Endothelial Cells; Endothelium; Etiology; Extracellular Matrix; Family suidae; Functional disorder; Funding; Goals; Growth Factor; Human; Hydrogels; Hypoxia; In Vitro; Knowledge; Lead; Learning; Life; Measurement; Measures; Medial; Mediating; Methods; Microcirculation; Microvascular Dysfunction; Modality; National Heart, Lung, and Blood Institute; Natural regeneration; Operative Surgical Procedures; Pathway interactions; Patient Care; Patients; Pericytes; Process; Prophylactic treatment; Public Health; Publishing; Recommendation; Regenerative Medicine; Research; Risk; Role; Rupture; Ruptured thoracic aortic aneurysm; Shapes; Signal Transduction; Specimen; Structure; Sudden Death; Techniques; Testing; Therapeutic Intervention; Thoracic Aortic Aneurysm; Tissues; Tunica Adventitia; Vascular Diseases; Vascular blood supply; Work; angiogenesis; base; bicuspid aortic valve; clinically significant; density; endothelial dysfunction; experience; high risk; human tissue; improved; in vivo; innovation; interest; meetings; mortality; mortality risk; novel; novel diagnostics; prevent; public health relevance; risk mitigation; stem cells; therapeutic target; tool; vasa vasorum; vasculogenesis

PROJECT SUMMARY Microvascular remodeling is an important contributor to vascular disease. Our team is broadly interested in how the extracellular matrix (ECM) affects microvascular function, and we are poised to make important contributions in this area to improve mechanistic understanding of human ascending aortic disease. The long-term goal of our work is to develop better strategies to diagnose and treat the over 2.5 million people affected worldwide by dissection and/or rupture of thoracic aortic aneurysm (TAA). We demonstrated that deficiency in angiogenic factors and collagen immaturity in the adventitial ECM are associated with vasa vasorum remodeling in degenerative and bicuspid aortic valve-associated TAA. These noted adventitial ECM disruptions in TAA helped to shape our central hypothesis that matrix cues in TAA provoke vasa vasorum dysfunction. Preliminary studies by our team revealed that hydrogel bioscaffolds made from adventitial ECM recapitulate native microstructure and retain signaling cues that invoke angiogenesis in vivo and endothelial cell proliferation and formation of branched networks in vitro. We will use human aortic tissue from early stages and multiple etiologies of TAA and porcine arteries to prepare ECM bioscaffolds from these tissues as biomimetic matrices of healthy and disease microenvironments. This approach optimally tests our central hypothesis at the whole vessel and cellular levels through execution of two specific aims. Aim 1) Determine how extracellular matrix of TAA affects remodeling and endothelial function of vasa vasorum; and Aim 2) Identify what matrix signals are necessary for regeneration of functional vasa vasorum. Under the first aim, we will comprehensively characterize the adventitial matrix of healthy aorta and various stages of human aneurysmal disease. We will then use ECM bioscaffolds derived from these human tissues to determine how matrix cues impact remodeling and endothelial function in isolated whole vessels of vasa vasorum and primary cultured human endothelial cells. Under the second aim, we will identify what growth factor-dependent and independent matrix cues regenerate functional vasa vasorum by pericytes isolated from TAA using in vitro and in vivo techniques. What we learn about vasa vasorum function in TAA could lead to the development of novel diagnostic approach that measure in vivo microvascular function in patients. Because aortic replacement remains the only treatment for ascending TAA, our work addresses an unmet clinical need to develop better therapies for TAA. Ultimately, the proposed research aspires to yield translational methods to understand, diagnose, and treat TAA, and therefore, improve patient-specific risk mitigation for aortic catastrophe. These approaches are innovative because they focus on aortic disease from perspective of the adventitial matrix which could lead to development of novel medicinal and regenerative medicine therapies and could help develop improved diagnostic measures for TAA.

项目摘要 微血管重构是血管疾病的重要原因。我们的团队广泛 感兴趣的是细胞外基质（ECM）如何影响微血管功能，我们准备使 在这一领域的重要贡献，以提高人类升主动脉疾病的机制的理解。 我们工作的长期目标是制定更好的战略来诊断和治疗250多万人 胸主动脉瘤（TAA）夹层和/或破裂的全球影响。我们证明了 血管生成因子的缺乏和外膜ECM中胶原的不成熟与血管生成有关。 退行性和二叶主动脉瓣相关TAA的血管重构。这些外膜ECM TAA的破坏有助于形成我们的中心假设，即TAA中的基质线索引发血管 功能障碍我们团队的初步研究表明，由外膜ECM制成的水凝胶生物支架 重现天然微结构并保留引起体内血管生成和内皮细胞 体外细胞增殖和分支网络的形成。我们将使用早期的人类主动脉组织 以及TAA和猪动脉的多种病因，以从这些组织制备ECM生物支架， 健康和疾病微环境的仿生基质。这种方法最佳地测试了我们的中央 在整个血管和细胞水平上通过执行两个特定的目标进行假设。目标1）确定 TAA细胞外基质如何影响血管重塑和血管内皮功能;目的2） 确定哪些基质信号是功能性血管再生所必需的。第一个目标，我们 将全面表征健康主动脉和人类各阶段的外膜基质 恶性疾病。然后，我们将使用来自这些人体组织的ECM生物支架，以确定如何 基质线索影响血管和原发性小血管的孤立的全血管的重塑和内皮功能 培养的人内皮细胞。在第二个目标下，我们将确定哪些生长因子依赖和 独立的基质线索再生功能性小血管的周细胞分离自TAA使用在体外和 体内技术。我们对TAA中血管功能的了解可能会导致新的 测量患者体内微血管功能的诊断方法。因为主动脉置换术 仍然是唯一的治疗上升TAA，我们的工作解决了一个未满足的临床需要，发展更好的 治疗TAA。最终，拟议的研究希望产生翻译方法来理解， 诊断和治疗TAA，从而改善主动脉灾难的患者特异性风险缓解。这些 这些方法是创新的，因为它们从外膜基质的角度关注主动脉疾病 这可能会导致新的医学和再生医学疗法的发展， 制定改进的TAA诊断措施。