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.
The bHLH TAL-1/SCL regulates endothelial cell migration and morphogenesis
Lazrak, M.; Deleuze, V.; Noel, D.; Haouzi, D.; Chalhoub, E.; Dohet, C.; Robbins, I.; Mathieu, D.
J Cell Sci
2004-03-01 / vol 117 / pages 1161-71
Cell Movement/physiology; Humans; Animals; Cells, Cultured; Mice; RNA, Small Interfering/genetics; Male; RNA Interference; Gene Expression Regulation, Developmental; Base Sequence; Cell Division; Sequence Deletion; Basic Helix-Loop-Helix Transcription Factors; DNA-Binding Proteins/chemistry/*genetics/*physiology; Endothelium, Vascular/*cytology/*growth & development/physiology; Helix-Loop-Helix Motifs; Mice, SCID; Neovascularization, Physiologic; Proto-Oncogene Proteins/chemistry/*genetics/*physiology; Transcription Factors/chemistry/*genetics/*physiology