Myocyte-endothelial signaling in angiogenesis

血管生成中的肌细胞内皮信号传导

• 批准号: 6445195
• 负责人: Robert D Rosenberg
• 金额: $ 21.93万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2001-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6445195
• 关键词: angiogenesis; angiogenesis factor; biological signal transduction; cardiac myocytes; cell communication molecule; cell migration; cell proliferation; genetically modified animals; heart circulation; laboratory mouse; microcirculation; myocardial infarction; platelet derived growth factor; tissue /cell culture; vascular endothelial growth factors; vascular endothelium

We have identified a set of unique microvascular endothelial cells (CMEC) comprising approximately 10-20% of cardiac EC in mice, that express the vWF2 transgene. The transgene is expressed only in the microvessels of the heart and brain. Utilizing a combination of vitro and in vivo techniques, we have reported that gene expression of VEGF, Flk- 1, and vWF is under the control of one or more soluble myocyte factor(s) which induce neighboring EC to produce the PDGF-B subunit. We have also demonstrated that the latter component, subsequently, combines with the constitutively expressed PDGF-A subunit to form the PDGF-AB heterodimer. The PDGF-AB heterodimer, in turn, interacts with cells that possess the PDGF-alpha receptor to initiate transcription of genes for VEGF, Flk-1, and vWF, which characterize this unique CMEC population. This study will employ this population of cells to examine the roles of soluble factors, novel gene products and novel cell surface components which serve to initiate the transcription of VEGF, Flk-1, TF and vWF via the PDGF-alpha Receptor Circuit and thereby initiated the migration and proliferation of these cells under in vitro conditions. The signaling circuit is unique in that it coordinates the expression of a number of angiogenic factors such that they can collectively act upon EC and CMEC. In addition, it employs tissue specific cells within the organ to control the function of the angiogenic cascade. We also propose to identify and characterize the soluble factors and novel gene products, other than vWF, VEGF and Flk-1 which are critical for CMEC proliferation and migration under in vitro conditions, and that initiate angiogenesis and cardiac microvessels and macrovessels under normal in vivo conditions as well as prior to and during myocardial infarction. These interactions provide a new paradigm in which the organ, itself, regulates the extent of it's own angiogenesis.

我们已经确定了一组独特的微血管内皮细胞（CMEC），其中约有小鼠心脏EC的10-20％，这些心脏EC表达了VWF2转基因。转基因仅在心脏和大脑的微血管中表达。利用体外和体内技术的组合，我们报道了VEGF，FLK-1和VWF的基因表达在一个或多个可溶性心肌细胞因子（S）的控制之下，这些因子（S）诱导附近的EC产生PDGF-B-B亚基。我们还证明，后一种分量随后与组成型表达的PDGF-A亚基相结合，形成PDGF-AB异二聚体。 PDGF-AB异二聚体反过来又与具有PDGF-Alpha受体的细胞相互作用，以启动VEGF，FLK-1和VWF的基因转录，这表征了这种独特的CMEC种群。这项研究将利用这些细胞群来检查可溶性因子，新型基因产物和新型细胞表面成分的作用，这些成分有助于通过PDGF-Alpha受体电路启动VEGF，FLK-1，TF和VWF的转录，从而在体外条件下启动这些细胞的迁移和扩散。信号电路的独特之处在于它可以协调许多血管生成因子的表达，从而可以集体对EC和CMEC作用。此外，它在器官内采用特定于组织的细胞来控制血管生成级联反应的功能。我们还建议识别和表征除VWF，VEGF和FLK-1以外的可溶性因子和新型基因产物，这对于在体外条件下对CMEC增殖和迁移至关重要，并且在正常情况下以及在正常情况下以及在心肌前后以及心肌内部以及心脏上以及心脏上的性行为。这些相互作用提供了一种新的范式，其中器官本身可以调节其自身的血管生成程度。