Morphogenesis of the pulmonary artery smooth muscle layer

肺动脉平滑肌层的形态发生

• 批准号: 8308488
• 负责人: Daniel Greif
• 金额: $ 13.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308488
• 关键词: Angioplasty; Apoptosis; Arteries; Atherosclerosis; Biological Assay; Blood Vessels; Boxing; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Confocal Microscopy; Coronary artery; Development; Disease; Elements; Embryo; Endothelial Cells; Event; Functional disorder; Goals; Hypertension; In Situ Hybridization; In Vitro; Indium; Investigation; Knockout Mice; LacZ Genes; Left; Left pulmonary artery; Ligands; Light; Lung; Lymphangioleiomyomatosis; Maintenance; Maps; Mediating; Mesenchymal; Molecular; Morphogenesis; Mus; Nutrient; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Physiological; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor alpha Receptor; Platelet-Derived Growth Factor beta Receptor; Play; Population; Process; Proteins; Proto-Oncogene Proteins c-sis; Pulmonary Hypertension; Pulmonary artery structure; Receptor Signaling; Reporter; Research Personnel; Rodent Model; Role; Seminal; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Staging; Staining method; Stains; Structure; Sum; TimeLine; Tissues; Transgenes; Transgenic Mice; Tube; Vascular Diseases; Work; cell motility; effective therapy; insight; lung development; molecular marker; programs; receptor; receptor expression; receptor-mediated signaling; research study; restenosis; transcription factor; vascular bed; vascular smooth muscle cell migration

Dedifferentiation and enhanced proliferation and motility of vascular smooth muscle cells (VSMCs) are key elements in the pathogenesis of many vascular diseases. Thus, a detailed understanding of the development of the VSMC layer of normal blood vessels promises to provide critical insights into vascular disease. However, the processes underlying the morphogenesis of any specific vessel or vascular bed are not well understood. The central goal of this proposal is to elucidate the key molecular and cellular events encompassing the morphogenesis of the smooth muscle cell (SMC) layer of the left pulmonary artery during the initial four days of murine lung development. This goal is the first step towards the long term objective of delineating the critical events in the building of all layers of the pulmonary artery throughout development. An essential element of achieving these goals is to characterize the roles specific signaling pathways play in pulmonary artery development. Platelet derived growth factor (PDGF)-induced signaling has been implicated in the pathogenesis of pulmonary artery hypertension and restenosis following coronary artery angioplasty; yet, the specific effects of PDGF signaling in these diseases or in the morphogenesis of large vessels remain elusive. I hypothesize that signaling through the PDGF pathway is critical for the maintenance, proliferation and/or recruitment of a multipoint early lung mesenchymal cell population that has the capacity to differentiate into the SMC layer of the left pulmonary artery. The proposal has three specific aims: 1) establish a timeline of molecular markers and cellular events that identify specific stages during the transition of a murine lung mesenchymal cell into a differentiated left pulmonary artery SMC and relate this timeline to'endothelial cell and non-vascular tissue development; 2) identify the pattern and effects of activation of PDGF receptor-mediated signaling pathways in left pulmonary artery SMC development; 3) determine the fate in the lung of early PDGF receptor-beta-positive mesenchymal cells through lineage analysis. To achieve these aims, lungs will be dissected from wildtype and transgenic mouse embryos and subjected to whole mount immunostaining, in situ hybridization or X-gal staining. In selected experiments, embryonic lungs will be cultured prior to analysis. Confocal microscopy will be used to analyze fluorescent stains on a cellular level. In sum, the proposed work will make the left pulmonary artery the best understood example of morphogenesis of a specific blood vessel. These studies will yield critical insights into the mechanisms underlying prevalent vascular diseases such as coronary artery atherosclerosis. In addition, this work promises to advance the investigation of critically understudied disorders of smooth muscle cell physiology in the lung, such as pulmonary artery hypertension and lymphangioleiomyomatosis.

血管平滑肌细胞（VSMCs）的去分化、增殖和运动性增强， 许多血管疾病发病机制中的关键因素。因此，详细了解 正常血管的VSMC层的发育有望为血管内皮细胞的研究提供重要的见解。 疾病然而，任何特定血管或血管床的形态发生的基础过程是 没有很好地理解。这项建议的中心目标是阐明关键的分子和细胞事件 包括左肺动脉平滑肌细胞（SMC）层的形态发生， 小鼠肺发育的最初四天。这一目标是实现长期目标的第一步， 描绘了整个发育过程中肺动脉各层构建的关键事件。 实现这些目标的一个基本要素是表征特定信号通路的作用 在肺动脉发育中的作用血小板衍生生长因子（PDGF）诱导的信号传导已被证实是一种重要的信号传导途径。 与肺动脉高压和冠状动脉再狭窄的发病机制有关 然而，PDGF信号在这些疾病或大血管形成中的具体作用， 船只仍然难以捉摸。我假设通过PDGF途径的信号传导对于 维持、增殖和/或募集多点早期肺间充质细胞群， 具有分化为左肺动脉SMC层的能力。 该提案有三个具体目标：1）建立分子标记和细胞事件的时间轴 识别小鼠肺间充质细胞向分化的左肺细胞转化过程中的特定阶段 肺动脉SMC，并将该时间轴与内皮细胞和非血管组织发育相关联; 2） 确定PDGF受体介导的信号通路激活的模式和作用， 动脉SMC的发展; 3）确定肺中的早期PDGF受体β阳性细胞的命运 间充质细胞通过谱系分析。为了实现这些目标，将从野生型中解剖肺， 和转基因小鼠胚胎，并进行整体包埋免疫染色、原位杂交或X-gal 染色在选定的实验中，将在分析前培养胚胎肺。共聚焦显微镜 将用于分析细胞水平上的荧光染色。 总之，所提出的工作将使左肺动脉成为最好理解的示例。 特殊血管的形态发生。这些研究将产生关键的见解的机制 潜在的流行性血管疾病，如冠状动脉粥样硬化。此外，这项工作 有望推进研究严重不足的平滑肌细胞生理学疾病， 肺，如肺动脉高压和淋巴管平滑肌瘤病。

项目成果

Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis.

• DOI: 10.1084/jem.20150688
• 发表时间: 2016-03-07
• 期刊: The Journal of experimental medicine
• 作者: Misra A;Sheikh AQ;Kumar A;Luo J;Zhang J;Hinton RB;Smoot L;Kaplan P;Urban Z;Qyang Y;Tellides G;Greif DM
• 通讯作者: Greif DM