Sangrar W, Mewburn J D, Vincent S G, Fisher J T, Greer P A
Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Ontario, Canada.
J Thromb Haemost. 2004 May;2(5):820-32. doi: 10.1111/j.1538-7836.2004.00654.x.
Fps/Fes is a cytoplasmic tyrosine kinase that is abundantly expressed in the myeloid, endothelial, epithelial, neuronal and platelet lineages. Genetic manipulation in mice has uncovered potential roles for this kinase in hematopoiesis, innate immunity, inflammation and angiogenesis.
We have utilized a genetic approach to explore the role of Fps/Fes in angiogenesis.
A hypervascular line of mice generated by expression of a 'gain-of-function' human fps/fes transgene (fps(MF)) encoding a myristoylated variant of Fps (MFps) was used in these studies. The hypervascular phenotype of this line was extensively characterized by intravital microscopy and biochemical approaches.
fps(MF) mice exhibited 1.6-1.7-fold increases in vascularity which was attributable to increases in the number of secondary vessels. Vessels were larger, exhibited varicosities and disorganized patterning, and were found to have defects in histamine-induced permeability. Biochemical characterization of endothelial cell (EC) lines derived from fps(MF) mice revealed that MFps was hypersensitive to activation by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).
MFps mediates enhanced sensitization to VEGF and PDGF signaling in ECs. We propose that this hypersensitization contributes to excessive angiogenic signaling and that this underlies the observed hypervascular phenotype of fps(MF) mice. These phenotypes recapitulate important aspects of the vascular defects observed in both VEGF and angiopoietin-1 transgenic mice. The fps/fes proto-oncogene product therefore represents a novel player in the regulation of angiogenesis, and the fps(MF) line of mice constitutes a unique new murine model for the study of this process.
Fps/Fes是一种细胞质酪氨酸激酶，在髓系、内皮、上皮、神经和血小板谱系中大量表达。对小鼠的基因操作揭示了该激酶在造血、先天免疫、炎症和血管生成中的潜在作用。
我们采用基因方法探讨Fps/Fes在血管生成中的作用。
在这些研究中使用了通过表达编码Fps肉豆蔻酰化变体（MFps）的“功能获得性”人fps/fes转基因（fps(MF)）产生的高血管化小鼠品系。通过活体显微镜和生化方法对该品系的高血管化表型进行了广泛表征。
fps(MF)小鼠的血管数量增加了1.6 - 1.7倍，这归因于二级血管数量的增加。血管更大，表现出静脉曲张和紊乱的模式，并发现其在组胺诱导的通透性方面存在缺陷。对源自fps(MF)小鼠的内皮细胞（EC）系的生化表征显示，MFps对血管内皮生长因子（VEGF）和血小板衍生生长因子（PDGF）的激活高度敏感。
MFps介导内皮细胞对VEGF和PDGF信号的增强敏感性。我们提出这种超敏反应导致过度的血管生成信号，这是观察到的fps(MF)小鼠高血管化表型的基础。这些表型概括了在VEGF和血管生成素-1转基因小鼠中观察到的血管缺陷的重要方面。因此，fps/fes原癌基因产物代表了血管生成调节中的一个新参与者，并且fps(MF)小鼠品系构成了研究这一过程的独特新小鼠模型。
