Lazrak Monia, Deleuze Virginie, Noel Danièle, Haouzi Delphine, Chalhoub Elias, Dohet Christiane, Robbins Ian, Mathieu Danièle
UMR 5535, Institut de Génétique Moléculaire, IFR122, 1919 Route de Mende, Montpellier, France.
J Cell Sci. 2004 Mar 1;117(Pt 7):1161-71. doi: 10.1242/jcs.00969. Epub 2004 Feb 17.
The basic helix-loop-helix tal-1 gene (or scl), known for its fundamental role in embryonic and adult hematopoiesis in vertebrates, is also required for embryonic vascular remodeling. In adults, TAL-1 protein is undetectable in quiescent endothelium but it is present in newly formed vessels including tumoral vasculature, indicating its involvement in angiogenesis. Here, we demonstrate that TAL-1 expression is tightly regulated during in vitro angiogenesis: it is low during the initial step of migration and is upregulated during formation of capillary-like structures. We investigated whether ectopic expression of either wild-type TAL-1 or a dominant-negative mutant lacking the DNA-binding domain (Delta-bas) modulates the activity of human primary endothelial cells in the angiogenic processes of migration, proliferation and cell morphogenesis. Overexpression of either wild-type or Delta-bas TAL-1 affected chemotactic migration of primary endothelial cells without modifying their proliferative properties. Ectopic expression of wild-type TAL-1 accelerated the formation of capillary-like structures in vitro and, in vivo, enhanced vascularisation in mice (Matrigel implants) associated with a general enlargement of capillary lumens. Importantly, transduction of the mutant Delta-bas completely impaired in vitro angiogenesis and strongly inhibited vascularisation in mice. Taken together, our data show that TAL-1 modulates the angiogenic response of endothelial cells by stimulating cell morphogenesis and by influencing their behavior in migration. This study highlights the importance of TAL-1 regulation in postnatal vascular remodeling and provides the first physiological evidence that links TAL-1 activity to endothelial cell morphogenic processes.
碱性螺旋-环-螺旋tal-1基因（或scl），因其在脊椎动物胚胎期和成年期造血过程中的重要作用而闻名，在胚胎血管重塑过程中也是必需的。在成体中，静止内皮细胞中检测不到TAL-1蛋白，但在包括肿瘤血管在内的新形成血管中存在，表明其参与血管生成。在此，我们证明TAL-1表达在体外血管生成过程中受到严格调控：在迁移的初始阶段表达较低，而在毛细血管样结构形成过程中上调。我们研究了野生型TAL-1或缺乏DNA结合结构域的显性负性突变体（Delta-bas）的异位表达是否会调节人原代内皮细胞在迁移、增殖和细胞形态发生等血管生成过程中的活性。野生型或Delta-bas TAL-1的过表达影响原代内皮细胞的趋化性迁移，但不改变其增殖特性。野生型TAL-1的异位表达在体外加速了毛细血管样结构的形成，在体内增强了小鼠的血管化（基质胶植入），同时伴有毛细血管腔普遍增大。重要的是，突变体Delta-bas的转导完全损害了体外血管生成，并强烈抑制了小鼠的血管化。综上所述，我们的数据表明TAL-1通过刺激细胞形态发生和影响其迁移行为来调节内皮细胞的血管生成反应。本研究突出了TAL-1调控在出生后血管重塑中的重要性，并提供了首个将TAL-1活性与内皮细胞形态发生过程联系起来的生理学证据。
