Pepper M S, Vassalli J D, Orci L, Montesano R
Department of Morphology, University Medical Center, Geneva, Switzerland.
Exp Cell Res. 1993 Feb;204(2):356-63. doi: 10.1006/excr.1993.1043.
Although the existence of an increasing number of angiogenesis-regulating cytokines is well documented, the response elicited by combinations of these cytokines is largely unknown. Using an in vitro model in which microvascular endothelial cells can be induced to form capillary-like tubes within three-dimensional collagen or fibrin gels, we have investigated the effect of transforming growth factor-beta 1 (TGF-beta 1) on basic fibroblast growth factor (bFGF)-induced and vascular endothelial growth factor (VEGF)-induced angiogenesis. Endothelial cell invasion and capillary lumen formation were inhibited by TGF-beta 1 at relatively high concentrations (5-10 ng/ml), while lower concentrations (100 pg/ml-1 ng/ml) of TGF-beta 1 potentiated the effect of bFGF- and VEGF-induced invasion. The optimal potentiating effect was observed at 200-500 pg/ml TGF-beta 1. At invasion-potentiating doses of TGF-beta 1, lumen size in fibrin gels was markedly reduced compared to that in cultures treated with bFGF alone. These results show that TGF-beta 1 exerts a biphasic effect on bFGF- and VEGF-induced angiogenesis in vitro. Our studies support the notion that the nature of the angiogenic response elicited by a specific cytokine is contextual, i.e., depends on the presence and concentration of other cytokines in the pericellular environment of the responding endothelial cell.
尽管越来越多的血管生成调节细胞因子的存在已得到充分证明，但这些细胞因子组合所引发的反应却 largely 未知。利用一种体外模型，在该模型中微血管内皮细胞可被诱导在三维胶原蛋白或纤维蛋白凝胶中形成毛细血管样管，我们研究了转化生长因子-β1（TGF-β1）对碱性成纤维细胞生长因子（bFGF）诱导的和血管内皮生长因子（VEGF）诱导的血管生成的影响。在相对高浓度（5 - 10 ng/ml）时，TGF-β1 抑制内皮细胞侵袭和毛细血管腔形成，而较低浓度（100 pg/ml - 1 ng/ml）的 TGF-β1 增强 bFGF 和 VEGF 诱导的侵袭作用。在 200 - 500 pg/ml 的 TGF-β1 时观察到最佳增强效果。在 TGF-β1 的侵袭增强剂量下，与仅用 bFGF 处理的培养物相比，纤维蛋白凝胶中的管腔大小明显减小。这些结果表明，TGF-β1 在体外对 bFGF 和 VEGF 诱导的血管生成发挥双相作用。我们的研究支持这样一种观点，即特定细胞因子引发的血管生成反应的性质是情境性的，即取决于响应内皮细胞周围环境中其他细胞因子的存在和浓度。
