The basic helix-loop-helix TAL-1/SCL essential for hematopoietic development is also required during vascular development for embryonic angiogenesis. We reported that TAL-1 acts positively on postnatal angiogenesis by stimulating endothelial morphogenesis. Here, we investigated the functional consequences of TAL-1 silencing in human primary endothelial cells. We found that TAL-1 knockdown caused the inhibition of in vitro tubulomorphogenesis, which was associated with a dramatic reduction in vascular endothelial cadherin (VE-cadherin) at intercellular junctions. Consistently, silencing of TAL-1 as well as of its cofactors E47 and LMO2 down-regulated VE-cadherin at both the mRNA and the protein level. Endogenous VE-cadherin transcription could be activated in nonendothelial HEK-293 cells by the sole concomitant ectopic expression of TAL-1, E47, and LMO2. Transient transfections in human primary endothelial cells derived from umbilical vein (HUVECs) demonstrated that VE-cadherin promoter activity was dependent on the integrity of a specialized E-box associated with a GATA motif and was maximal with the coexpression of the different components of the TAL-1 complex. Finally, chromatin immunoprecipitation assays showed that TAL-1 and its cofactors occupied the VE-cadherin promoter in HUVECs. Together, these data identify VE-cadherin as a bona fide target gene of the TAL-1 complex in the endothelial lineage, providing a first clue to TAL-1 function in angiogenesis.

The 2 related basic helix loop helix genes, LYL1 and TAL-1 are active in hematopoietic and endothelial lineages. While Tal-1 is essential for both hematopoietic and vascular development, the role of Lyl1 appears to be distinct as deficient mice are viable and display modest hematopoietic defects. Here, we reveal a role for Lyl1 as a major regulator of adult neovascularization. Tumors implanted into Lyl1-deficient mice showed higher proliferation and angiogenesis, as evidenced by enlarged lumens, reduced pericyte coverage and increased permeability, compared with wild type littermates. Of note, Lyl1-deficient tumor vessels exhibited an up-regulation of Tal-1, the VE-Cadherin target gene, as well as Angiopoietin-2, 3 major actors in angiogenesis. Hematopoietic reconstitution experiments demonstrated that this sustained tumor angiogenesis was of endothelial origin. Moreover, the angiogenic phenotype observed in the absence of Lyl1 function was not tumor-restricted as microvessels forming in Matrigel or originating from aortic explants were also more numerous and larger than their wild-type counterparts. Finally, LYL1 depletion in human endothelial cells revealed that LYL1 controls the expression of molecules involved in the stabilization of vascular structures. Together, our data show a role for LYL1 in the postnatal maturation of newly formed blood vessels. (Blood. 2010; 115(25):5270-5279) IntroductionThe vascular system through development and adulthood answers to injury and remodeling and is one of the key systems sustaining normal physiology. Conversely, its deregulation also underlies multiple pathologic processes such as ischemia, inflammation and tumor. Angiogenesis normally occurs as a sequential series of morphogenetic events resulting in a functional network of vessels. Regulation of endothelial cell function in all these processes requires the integration of complex signals by the coordinated action of specific transcription factors.LYL1 is a member of the large basic helix loop helix (bHLH) family, and is closely related to TAL-1 (also called SCL). Both LYL1 and TAL-1 were identified through their involvement in chromosomal rearrangements in human T-cell leukemia (reviewed in Baer 1 ). Tal-1 deficiency causes embryonic lethality due to the absence of hematopoietic cell formation [2][3][4][5] and several studies have shown that Tal-1 is also involved in the formation of the vascular system. 6-10 Unlike Tal-1, Lyl1 is not essential for developmental processes, since homozygous disruption of Lyl1 activity induces only a mild hematopoietic phenotype. 11 The viable Lyl1-deficient mice display a reduced number of B cells and impaired long-term hematopoietic reconstitution capacity. 11 The highly conserved bHLH motifs between TAL-1 and LYL1 are functionally interchangeable to restore immature hematopoiesis in Tal-1 deficient embryonic stem cells. 4,12 Moreover, Tal-1 and Lyl1 display redundant activities to maintain adult hematopoietic stem cell functions. 13 However, full-length LYL1 cannot rescue early letha...