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的病理生物学并寻找减少肺闭塞的方法 动脉。目前的应用表明，血管内皮干细胞 (VESC)通过失控的细胞生长和内皮细胞向间充质细胞的转化导致PAH (EndoMT)。研究结果表明，VESC移植合并慢性缺氧会导致 肺动脉闭塞和重度PAH。这种方法是作为一种新颖的VESC提出的。 聚焦性PAH动物模型。更多的初步数据表明，在没有 成纤维细胞生长因子-2与血管内皮细胞在转化过程中的内源性MT 生长因子β(转化生长因子-β)。鉴于这些值得注意的发现，假设VESC导致PAH与 两种主要方式造成的类似人类PAH的血管病变：无节制的增殖驱动 在转化生长因子-β存在的情况下，通过血管内皮细胞生长因子-2和血管内皮细胞移植。提出了三个具体的目标来测试 假说：目标1：确定在生理学、组织学和基因表达方面的动态变化 VESC诱导的PAH。目的：探讨成纤维细胞生长因子-2在血管内皮细胞无抑制生长中的作用。 啊哈。目的3：探讨转化生长因子-β对血管内皮细胞内源性MT在肺动脉高压中的作用。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，一种新的VESC模型-- 将对诱发的PAH进行评估，并将结果与已知的生理学、组织学和 帕金森病患者的基因表达谱。那么，成纤维细胞生长因子-2在血管内皮细胞中的作用 在体外和体内通过阻断成纤维细胞生长因子-2来评估细胞的增殖情况。最后，转化生长因子-β的贡献 在体外和体内实验中，将通过阻断转化生长因子-β来测试TO对多环芳烃的抑制作用。本研究 本研究在两个方面具有创新性：(1)首次对VESC作为失控原因进行了研究 PAH的细胞生长和内源性MT；(2)这些实验将改进现有的动物模型，通过 将标记的VESC克隆与慢性缺氧相结合。初步数据表明，这样的战略 将导致一种新的、独特的PAH模型。这种模式的强大之处在于它起源于一种致病 IPAH的概念：VESC的克隆性扩张导致肺动脉闭塞。它是 期待这样的研究将开始揭示为什么VESC不能修复血管，而是导致 啊哈。预计这些结果将有助于制定减少多环芳烃的战略，同时 通过VESC促进血管修复。这样的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。因此， 拟议的研究与发展基础知识有关，这将有助于减少 心肺疾病的负担。

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.