Antoine M, Wirz W, Tag C G, Gressner A M, Wycislo M, Müller R, Kiefer P
Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen, Germany.
Biochem Biophys Res Commun. 2006 Jul 21;346(1):224-33. doi: 10.1016/j.bbrc.2006.05.105. Epub 2006 May 26.
Endothelial cells line the blood vessel and precursor endothelial cells appear to have a pivotal effect on the organ formation of the heart, the embryonic development of the kidney, and the liver. Several growth factors including the fibroblast growth factors (FGF) seem to be involved in these processes. Ligands such as basic FGF produced and secreted by endothelial cells may also coordinate cellular migration, differentiation, and proliferation under pathological conditions including wound healing, tumorgenesis, and fibrogenesis in the adult. Recently we demonstrated the expression of two secreted FGFs, FGF16, and FGF18, in HUVEC and in rat aortic tissue. In the present report, we confirmed by RT-PCR analysis that FGF18 is wildly expressed in the cardiovascular tissue, while FGF16 showed a more restricted expression pattern. HUVEC clearly demonstrated chemotaxis towards FGF16 and FGF18. Both FGFs also enhanced cell migration in response to mechanical damage. However, recombinant FGF16 and FGF18 failed to induce endothelial cell proliferation or sprouting in a three-dimensional in vitro angiogenesis assay. Fgf18 expression was earlier reported in the liver, and we detected FGF18 expression in liver vascular and liver sinusoidal endothelial cells (LSECs), but not in hepatic parenchymal cells. Recombinant FGF18 stimulated DNA synthesis in primary hepatocytes, suggesting, that endothelial FGF18 might have a paracrine function in promoting growth of the parenchymal tissue. Interestingly, FGF2, which is mitogenic on endothelial cells and hepatocytes stimulates a sustained MAPK activation in both cell types, while FGF18 causes a short transient activation of the MAPK pathway in endothelial cells but a sustained activation in hepatocytes. Therefore, the difference in the time course of MAPK activation by the different FGFs appears to be the cause for the different cellular responses.
内皮细胞排列在血管内壁，前体内皮细胞似乎对心脏的器官形成、肾脏的胚胎发育以及肝脏有着关键作用。包括成纤维细胞生长因子（FGF）在内的多种生长因子似乎都参与了这些过程。内皮细胞产生并分泌的配体，如碱性FGF，在包括伤口愈合、肿瘤发生和成人纤维生成在内的病理条件下，也可能协调细胞迁移、分化和增殖。最近我们证明了两种分泌型FGF，即FGF16和FGF18，在人脐静脉内皮细胞（HUVEC）和大鼠主动脉组织中的表达。在本报告中，我们通过逆转录聚合酶链反应（RT-PCR）分析证实，FGF18在心血管组织中广泛表达，而FGF16的表达模式则更为局限。HUVEC对FGF16和FGF18表现出明显的趋化性。这两种FGF还能增强细胞对机械损伤的迁移反应。然而，在三维体外血管生成试验中，重组FGF16和FGF18未能诱导内皮细胞增殖或出芽。Fgf18的表达此前在肝脏中已有报道，我们在肝血管和肝窦内皮细胞（LSEC）中检测到了FGF18的表达，但在肝实质细胞中未检测到。重组FGF18刺激原代肝细胞中的DNA合成，这表明内皮FGF18可能在促进实质组织生长方面具有旁分泌功能。有趣的是，FGF2对内皮细胞和肝细胞具有促有丝分裂作用，能在两种细胞类型中刺激持续的丝裂原活化蛋白激酶（MAPK）激活，而FGF18在内皮细胞中引起MAPK途径的短暂瞬时激活，但在肝细胞中引起持续激活。因此，不同FGF激活MAPK的时间进程差异似乎是导致不同细胞反应的原因。
