Modeling Von Willebrand Factor Behavior in the Pulmonary Circulation in Health and Disease

项目摘要 肺动脉高压（PAH）是一种高度病态的疾病，其病理特征是肺动脉高压。 动脉和小动脉微血栓形成、血管收缩以及内膜和中膜增生。的机制 潜在的PAH发生和进展仍不完全清楚。探潜小说 PAH的贡献者将有助于疾病的理解和新的治疗靶点的开发。 有证据表明，内皮激活在PAH的发病机制中起着至关重要的作用。一个重要 内皮细胞活化的早期结果是血管性血友病因子（vonWillebrand Factor，VWF）从内皮细胞中释放， 细胞通过胞吐预先形成的细胞器称为韦伯-帕拉德体（WPB）。VWF介导结合 在内皮和循环血液成分如血小板之间， 血栓形成和炎症。VWF导致人类疾病中的血管功能障碍，包括 动脉粥样硬化、静脉血栓形成、败血症和血栓性微血管病。PAH患者 循环VWF水平增加，多聚体组成改变，并显示VWF染色增加 在尸检时发现了肺内皮细胞循环VWF水平与PAH的疾病严重程度相关。 在体循环的研究中，VWF促进微血管血栓形成，平滑肌细胞 增殖和血小板的募集。所有这些过程都与PAH有关，VWF的分泌可能 因此导致PAH的疾病进展。郑颖博士创造了内皮化生物工程 微血管概括了微血管的结构和流动条件，并允许使用 确定来源的人体组织。这项研究计划的重点是应用郑实验室的微血管模型 研究VWF在肺循环中的行为。这个拟议的项目将描述表达的特征 和VWF在肺内皮内的储存，导致VWF释放的环境因素，以及 VWF释放对肺血管内皮和肺血管平滑肌的下游作用 肌肉.本研究计划包括三个主要目的：（1）研究VWF的表达、储存和分泌 （2）评价PAH中观察到的环境条件如何影响 VWF的表达、储存和释放（3）检查VWF释放增加对血管内皮细胞的影响。 重塑这项研究将为今后研究VWF的下游作用机制奠定基础 对肺血管系统的影响，并可能导致VWF靶向治疗的发展， 治疗PAH。由于VWF也与许多全身性血管疾病有关，因此这项研究可能会 在肺血管生物学之外具有广泛的应用。

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized pathologically by pulmonary arterial and arteriolar microthrombosis, vasoconstriction, and intimal and medial hyperplasia. The mechanisms underlying PAH initiation and progression remain incompletely understood. Exploring potential novel contributors to PAH will aid in disease understanding and the development of new therapeutic targets. Evidence suggests that endothelial activation plays a crucial role in the pathogenesis of PAH. An important early consequence of endothelial activation is the release of von Willebrand Factor (VWF) from endothelial cells via exocytosis of pre-formed organelles known as Weibel-Palade bodies (WPB). VWF mediates binding between the endothelium and circulating blood components such as platelets, and promotes microvascular thrombosis and inflammation. VWF contributes to vascular dysfunction in human diseases including atherosclerosis, venous thrombosis, sepsis, and the thrombotic microangiopathies. Patients with PAH have increased levels of circulating VWF with altered multimer composition, and display increased staining for VWF within the pulmonary endothelium on autopsy. Circulating VWF levels correlate with disease severity in PAH. In studies of the systemic circulation, VWF promotes microvascular thrombosis, smooth muscle cell proliferation, and recruitment of platelets. All these processes are involved in PAH, and VWF secretion may therefore contribute to disease progression in PAH. Dr. Ying Zheng has created endothelialized bioengineered microvessels that recapitulate the architecture and flow conditions of the microvasculature and allow use of human tissues of defined origin. This research proposal focuses on applying the Zheng lab microvessel model to study VWF's behavior in the pulmonary circulation. This proposed project will characterize the expression and storage of VWF within the pulmonary endothelium, the environmental factors leading to VWF release, and the downstream effects of VWF release on the pulmonary endothelium and pulmonary vascular smooth muscle. This research proposal comprises three main aims: (1) Study VWF expression, storage, and secretion in cells of different pulmonary vascular origin (2) Evaluate how environmental conditions seen in PAH affect VWF expression, storage, and release (3) Examine the consequences of increased VWF release on vascular remodeling. This research will set the stage for future mechanistic studies on the downstream effects of VWF on the pulmonary vasculature, and may lead to the development of VWF-targeted therapeutics for the treatment of PAH. As VWF is also implicated in numerous systemic vascular diseases, this research is likely to have broad application beyond pulmonary vascular biology.