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（VSMC）的去分化和增强和运动性增强和运动性是 许多血管疾病的发病机理中的关键因素。因此，对 正常血管VSMC层的发展有望为血管提供关键的见解 疾病。但是，任何特定血管或血管床形态发生的过程是 不太了解。该建议的核心目标是阐明关键分子和细胞事件 涵盖左肺动脉平滑肌细胞（SMC）层的形态发生 鼠肺发育的最初四天。这个目标是朝着长期目标迈出的第一步 在整个发育过程中描述建造肺动脉所有层的关键事件。 实现这些目标的一个重要因素是表征特定角色的特定信号通路 玩肺动脉发育。血小板衍生的生长因子（PDGF）诱导的信号传导已是 与冠状动脉后肺动脉高血压和再狭窄的发病机理有关 血管成形术；然而，PDGF信号传导在这些疾病或大型形态发生中的特定作用 船只仍然难以捉摸。我假设通过PDGF途径传导对于 维持，增殖和/或募集多点早期肺间充质细胞群 具有区分左肺动脉的SMC层的能力。 该提案具有三个特定的目的：1）建立分子标记和细胞事件的时间表 在鼠肺间充质细胞过渡到分化的左侧的过渡期间，识别特定阶段 肺动脉SMC并将该时间轴与“内皮细胞”和非血管组织发育联系起来； 2） 确定左肺中PDGF受体介导的信号通路激活的模式和影响 动脉SMC开发； 3）确定早期PDGF受体β阳性的肺中的命运 间充质细胞通过谱系分析。为了实现这些目标，将从野生型中剖析肺 和转基因小鼠胚胎，并进行整个固定免疫染色，原位杂交或x-gal 染色。在选定的实验中，胚胎肺将在分析前进行培养。共聚焦显微镜 将用于分析细胞水平上的荧光污渍。 总而言之，拟议的工作将使左肺动脉成为最好的理解的例子 特定血管的形态发生。这些研究将对机制产生关键的见解 潜在的流行血管疾病，例如冠状动脉粥样硬化。此外，这项工作 有望提高对平滑肌细胞生理的严格研究疾病的研究 肺，例如肺动脉高血压和淋巴血管瘤病。

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