Wernert Nicolas, Okuducu Ali-Fuat, Pepper Michael S
Institute of Pathology, University of Bonn, PO Box 2120, 53011 Bonn, Germany.
J Pathol. 2003 Aug;200(5):561-7. doi: 10.1002/path.1380.
Little is known about the mechanisms that regulate lymphangiogenesis and, in particular, about regulation at the transcriptional level. To determine whether parallels exist in the mechanisms of angiogenesis and lymphangiogenesis, the expression of the Ets 1 transcription factor (which has previously been shown to be involved in angiogenesis) was examined in two transgenic mouse lines, namely RipVEGF-C mice (which develop lymphatic capillaries ectopically around islets of Langerhans) and Rip1Tag2 mice (which develop insulinomas that are not lymphangiogenic). Crossing the two lines results in double transgenic mice that develop lymphatics around insulinomas, which in turn promotes metastasis to regional lymph nodes. By immunohistochemistry, it was found that, in contrast to blood vessels, lymphatic vessels in wild-type and transgenic mice did not express Ets 1. Immunohistochemical staining for matrix metalloproteinase (MMP)-2 and MMP-9 as well as membrane type 1-MMP (MT1-MMP/MMP-14), all of which are encoded by known or potential Ets 1 target genes, showed the same cellular distribution as Ets 1. These findings suggest that the transcriptional regulatory mechanisms of lymphangiogenesis differ from those involved in angiogenesis. Furthermore, if proteases are involved in lymphangiogenesis, these observations suggest that they are different from those considered to be important for blood vessel formation.
关于调节淋巴管生成的机制，尤其是转录水平的调节，我们知之甚少。为了确定血管生成和淋巴管生成机制中是否存在相似之处，我们在两种转基因小鼠品系中检测了Ets 1转录因子（先前已证明其参与血管生成）的表达，即RipVEGF-C小鼠（在胰岛周围异位形成淋巴管）和Rip1Tag2小鼠（形成不发生淋巴管生成的胰岛素瘤）。将这两种品系杂交产生双转基因小鼠，其在胰岛素瘤周围形成淋巴管，进而促进向区域淋巴结转移。通过免疫组织化学发现，与血管不同，野生型和转基因小鼠的淋巴管不表达Ets 1。对基质金属蛋白酶（MMP）-2、MMP-9以及膜型1-MMP（MT1-MMP/MMP-14）进行免疫组织化学染色，所有这些均由已知或潜在的Ets 1靶基因编码，结果显示它们与Ets 1具有相同的细胞分布。这些发现表明，淋巴管生成的转录调控机制与血管生成的不同。此外，如果蛋白酶参与淋巴管生成，这些观察结果表明它们与那些被认为对血管形成很重要的蛋白酶不同。
