Vega-Diaz B, Herron G S, Michel S
Galderma R&D, Sophia Antipolis, Valbonne, France.
J Invest Dermatol. 2001 Apr;116(4):525-30. doi: 10.1046/j.1523-1747.2001.01294.x.
The expression of vascular endothelial growth factor mRNA and protein is regulated by a number of agents including growth factors, cytokines, and phorbol esters. Here we report that vascular endothelial growth factor is able to increase its own level in cultured human dermal microvascular endothelial cells. Accumulation of vascular endothelial growth factor mRNA and polypeptide can be detected as early as 4 h after addition of vascular endothelial growth factor to the cell culture medium. The autocrine action of vascular endothelial growth factor appears to be mediated by the KDR receptor. The increase of its own message by vascular endothelial growth factor is blocked by the transcription inhibitor actinomycin D. Transient transfection experiments performed with human dermal microvascular endothelial cells and using a 3.2 kb human vascular endothelial growth factor promoter fragment showed that vascular endothelial growth factor auto-induction can be mimicked at the promoter level. This indicates that the observed vascular endothelial growth factor mRNA increase after vascular endothelial growth factor treatment is occurring at the level of transcription. Furthermore, vascular endothelial growth factor auto-induction is inhibited by PD 098059, showing that phosphorylation events, catalyzed by mitogen activated protein kinases, are a prerequisite for the vascular endothelial growth factor effect. Examination of extracellular signal-regulated kinase and c-Jun N-terminal protein kinase catalytic activities showed that both enzymes have to be activated to mediate the vascular endothelial growth factor signal. Our data demonstrate for the first time the existence of an autocrine loop for vascular endothelial growth factor in endothelial cells. Most probably this represents an amplification mechanism for the action of vascular endothelial growth factor in the microvascularization process.
血管内皮生长因子mRNA和蛋白质的表达受多种因素调控，包括生长因子、细胞因子和佛波酯。在此我们报告，血管内皮生长因子能够在培养的人真皮微血管内皮细胞中提高其自身水平。早在向细胞培养基中添加血管内皮生长因子后4小时，就能检测到血管内皮生长因子mRNA和多肽的积累。血管内皮生长因子的自分泌作用似乎是由KDR受体介导的。血管内皮生长因子对其自身信使的增加被转录抑制剂放线菌素D阻断。用人真皮微血管内皮细胞并使用3.2 kb人血管内皮生长因子启动子片段进行的瞬时转染实验表明，在启动子水平上可以模拟血管内皮生长因子的自诱导。这表明在血管内皮生长因子处理后观察到的血管内皮生长因子mRNA增加发生在转录水平。此外，血管内皮生长因子的自诱导被PD 098059抑制，表明丝裂原活化蛋白激酶催化的磷酸化事件是血管内皮生长因子发挥作用的先决条件。对细胞外信号调节激酶和c-Jun N末端蛋白激酶催化活性的检测表明，这两种酶都必须被激活才能介导血管内皮生长因子信号。我们的数据首次证明内皮细胞中存在血管内皮生长因子的自分泌环。这很可能代表了血管内皮生长因子在微血管形成过程中作用的一种放大机制。
