Matrix mediated vasa vasorum dysfunction in thoracic aortic disease

项目总结 微血管重塑是导致血管疾病的重要因素。我们的团队是广泛的 对细胞外基质(ECM)如何影响微血管功能感兴趣，我们准备 在这一领域的重要贡献，提高了对人类升主动脉疾病的机制认识。 我们工作的长期目标是制定更好的战略来诊断和治疗超过250万人 世界范围内受胸主动脉瘤(TAA)夹层和/或破裂影响。我们证明了这一点 血管生成因子缺乏和外膜ECM中的胶原不成熟与血管相关 退行性和二尖瓣相关的TAA中的血管重构。这些注意到的外膜ECM TAA中的干扰帮助形成了我们的中心假设，即TAA中的基质线索刺激血管 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 概括自然微结构并保留激活体内和内皮细胞血管生成的信号线索 细胞在体外的增殖和分枝网络的形成。我们将使用早期的人主动脉组织 和多种病因的TAA和猪动脉从这些组织制备ECM生物支架 健康和疾病微环境的仿生基质。这种方法最好地测试了我们的中央 通过执行两个特定的目标，在全血管和细胞水平上的假设。目标1)确定 TAA细胞外基质对血管重塑和内皮功能的影响 确定哪些基质信号是功能性血管再生所必需的。在第一个目标下，我们 将全面表征健康的大动脉和人类不同阶段的外膜基质 动脉瘤样疾病。然后，我们将使用从这些人体组织中提取的ECM生物支架来确定 基质信号对分离的全血管和原发血管重塑和内皮功能的影响 培养的人内皮细胞。在第二个目标下，我们将确定哪些增长因子依赖和 独立的基质信号通过从TAA分离的周细胞在体外和 活体技术。我们对TAA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 仍然是治疗上升TAA的唯一方法，我们的工作解决了尚未满足的临床需求，以发展得更好 治疗TAA的方法。最终，拟议的研究立志于产生理解的翻译方法， 诊断和治疗TAA，因此，改善患者特定的主动脉灾难风险缓解。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，并可能有助于 制定改进的TAA诊断方法。

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.