Central role of endothelial stem cells in pulmonary arterial hypertension

目前的肺动脉高压（PAH）动物模型存在局限性， 了解PAH病理生物学并确定减少肺动脉闭塞的方法 动脉目前的应用表明，血管内皮干细胞 （VESC）通过不受控制的细胞生长和内皮-间质转化引起PAH （EndoMT）。研究结果表明，VESC移植联合慢性缺氧导致 肺动脉闭塞和重度PAH。这种方法在这里提出了一种新的VESC- 针对PAH的动物模型。额外的初步数据表明，VESC增殖较少， 成纤维细胞生长因子-2（FGF-2）和VESC在转化存在下经历EndoMT 生长因子-β（TGF-β）。鉴于这些显著的发现，假设VESC引起PAH， 类似于人类PAH的血管病变通过两种主要方式：未经检查的增殖驱动 通过FGF-2和EndoMT在TGF-β的存在下。提出了三个具体目标，以测试 假设：目的1：确定在生理学，组织学和基因表达的动态变化， VESC诱导的PAH。目的2：研究FGF-2在VESC无抑制生长中的作用， 呸。目的3：探讨TGF-β在肺动脉高压（PAH）中对内皮细胞内MT表达的影响。为了实现这些目标，在 将使用克隆选择的VESC进行体外和体内实验。首先，VESC的新模式- 将评价诱导的PAH，并将结果与已知的生理学、组织学和 PAH患者中确定的基因表达谱。那么，FGF-2在VESC中的作用 通过在体外和体内阻断FGF-2来评价增殖。最后，TGF-β的作用 将通过在体外和体内实验中阻断TGF-β来测试EndoMT对PAH的影响。本研究 本研究的创新之处在于：（1）首次探讨了VESC作为未检查的原因 PAH中的细胞生长和EndoMT;（2）这些实验将通过以下方式改善现有的动物模型： 将标记的VESC克隆与慢性缺氧组合。初步数据显示， 将导致一种新的独特的PAH模型。这个模型的优势在于它起源于一种致病的 iPAH的概念：VESC的克隆性扩增导致肺动脉闭塞。是 期望这些研究将开始揭示为什么VESC不能修复血管，而是导致 呸。预计这些结果将有助于制定减少PAH的策略，同时 通过VESC促进血管修复。这些数据有望帮助寻找新的药物靶点。 根据这些数据进行的进一步研究可能会降低PAH患者的死亡率。所以 拟议的研究与发展基础知识有关，这将有助于减少 心肺疾病负担。

Current animal models of pulmonary arterial hypertension (PAH) have shortcomings that limit understanding of PAH pathobiology and identifying approaches to reduce occlusion of pulmonary arteries. The current application shows findings that indicate that vascular endothelial stem cells (VESC) cause PAH through uncontrolled cell growth and endothelial-to-mesenchymal transition (EndoMT). The findings are that VESC transplantation combined with chronic hypoxia leads to occlusion of pulmonary arteries and severe PAH. This approach is here proposed as a novel VESC- focused animal model of PAH. Additional preliminary data suggest that VESC proliferate less without fibroblast growth factor-2 (FGF-2) and that VESC undergo EndoMT in the presence of transforming growth factor-β (TGF-β). Given these remarkable findings, the hypothesis is VESC cause PAH with vascular lesions resembling human PAH via two main means: unchecked proliferation driven by FGF-2 and EndoMT in the presence of TGF-β. Three specific aims are proposed to test the hypothesis: Aim 1: To define dynamic changes in physiology, histology and gene expression in VESC-induced PAH. Aim 2: To investigate the role of FGF-2 for unchecked growth of VESC in PAH. Aim 3: To identify the role of TGF-β for EndoMT of VESC in PAH. To achieve these aims, in vitro and in vivo experiments using clonally selected VESC will be used. First, a new model of VESC- induced PAH will be evaluated and the results will be compared with known physiology, histology and gene expression profile as identified in patients with PAH. Then, the role of FGF-2 in VESC proliferation will be evaluated by blocking FGF-2 in vitro and in vivo. Finally, the contribution of TGF-β to EndoMT for PAH will be testing by blocking TGF-β in in vitro and in vivo experiments. This study is innovative in two aspects: (1) this is the first study to investigate VESC as cause of unchecked cell growth and EndoMT in PAH; (2) these experiments will improve upon existing animal models by combining labeled VESC clones with chronic hypoxia. Preliminary data suggest that such a strategy will lead to a new and unique model of PAH. The strength of this model is its origin from a pathogenic concept for iPAH: clonal expansion of VESC causes occlusion of pulmonary arteries. It is the expectation that such studies will start to reveal why VESC fail to repair vessels and instead cause PAH. Such results are expected to help developing strategies to reduce PAH and at the same time to foster vascular repair by VESC. Such data are then expected to help finding new drug targets. Further research resulting from these data could reduce mortality in PAH patients. Hence, the proposed research is pertinent to developing fundamental knowledge that will help to reduce the burden of cardiopulmonary disease.