Myocyte-endothelial signaling in angiogenesis

我们已经鉴定出一组独特的微血管内皮细胞（CMEC），其表达vWF2转基因，约占小鼠心脏EC的10-20%。转基因只在心脏和大脑的微血管中表达。利用体外和体内技术的结合，我们报道了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，这些因子诱导邻近的EC产生PDGF-B亚基。我们还证明，后一组分随后与组成性表达的PDGF-A亚基结合形成PDGF-AB异源二聚体。反过来，PDGF-AB异源二聚体与拥有pdgf - α受体的细胞相互作用，启动VEGF、Flk-1和vWF基因的转录，这些基因是这种独特的CMEC群体的特征。本研究将利用这一细胞群来研究可溶性因子、新基因产物和新细胞表面成分的作用，这些因子通过pdgf - α受体回路启动VEGF、Flk-1、TF和vWF的转录，从而启动这些细胞在体外条件下的迁移和增殖。信号通路的独特之处在于它协调许多血管生成因子的表达，使它们能够共同作用于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。除了vWF、VEGF和Flk-1外，我们还建议鉴定和表征在体外条件下对CMEC增殖和迁移至关重要的可溶性因子和新的基因产物，并在体内正常条件下以及心肌梗死之前和期间启动血管生成和心脏微血管和大血管。这些相互作用提供了一种新的模式，即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.