Myocyte-endothelial signaling in angiogenesis

我们已经确定了一组独特的微血管内皮细胞（CMEC），其中约10-20%的小鼠心脏EC，表达vWF 2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，我们已经报道了VEGF、Flk- 1和vWF的基因表达受一种或多种可溶性肌细胞因子的控制，这些因子诱导邻近EC产生PDGF-B亚基。我们还证明，后者的组成成分，随后，结合组成型表达的PDGF-A亚基，形成PDGF-AB异二聚体。PDGF-AB异二聚体反过来与具有PDGF-alpha受体的细胞相互作用，以启动VEGF、Flk-1和vWF基因的转录，这些基因是这种独特CMEC群体的特征。本研究将使用该细胞群体来检查可溶性因子、新型基因产物和新型细胞表面组分的作用，这些因子、新型基因产物和新型细胞表面组分用于通过PDGF-α受体回路启动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增殖。信号传导回路是独特的，因为它协调许多血管生成因子的表达，使得它们可以共同作用于EC和CMEC。此外，它利用器官内的组织特异性细胞来控制血管生成级联的功能。我们还提出了确定和表征的可溶性因子和新的基因产物，而不是vWF，VEGF和Flk-1，这是至关重要的CMEC增殖和迁移在体外条件下，并启动血管生成和心脏微血管和大血管在正常的体内条件下，以及之前和心肌梗死期间。这些相互作用提供了一个新的范例，其中器官本身调节其自身血管生成的程度。

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.