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Home page > Research Groups > Danièle MATHIEU - Transcriptional Control of Angiogenesis

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Danièle MATHIEU - Transcriptional Control of Angiogenesis

In adults, the formation of new vessels or angiogenesis is required in rare physiological situations, but it occurs in pathological situations such as inflammatory diseases and tumors, where it aggravates the evolution of these pathologies. Our projects aim at identifying the mechanisms and molecular actors that mediate the response of the endothelial cells (EC) to environment signals, such as angiogenic ones. More particularly, our program research focuses on the function of two highly related bHLH transcription factors, TAL-1 and LYL1, the expression of which is limited to 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. We previously reported that TAL-1 expression is associated with angiogenic endothelial phenotype, whereas LYL1 expression correlates with mature and quiescent blood vessels.

TAL-1 stimulates angiogenesis through up regulation of important angiogenic molecules. We previously demonstrated that TAL-1 activity is modulated during experimental angiogenesis of adult ECs, with a significant up regulation during the morphogenetic events leading to the formation of capillary-like networks. Conversely, TAL-1 is down regulated when ECs enter quiescence induced by cellular confluence associated with angiogenic factor starvation. Gain and loss of function experiments in mice (model of subcutaneous Matrigel plugs) identified that ectopic TAL-1 expression stimulates angiogenesis, while inhibiting its activity completely impaired this process. Furthermore, we found that TAL-1 is required to initiate endothelial morphogenesis, where it directly activates, together with LMO2 and E47, the expression of VE-cadherin, the major constituent of adherens junctions. In agreement, we reported that dynamic fluctuations of TAL-1 and its partners on the VE-cadherin promoter contribute to the precise timing of VE-cadherin expression in ECs.

LYL1 is required for stabilization of developing blood vessels in adulthood. We recently revealed 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, as compared to wild type littermates. Of note, Lyl1-deficient tumor vessels exhibited an up-regulation of Tal-1, its VE-Cadherin target gene, as well as Angiopoietin-2, three major actors in angiogenesis. Importantly, 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.

Identification of the molecular targets (genes and signalization pathways) downstream of both TAL-1 and LYL1. Current analysis of the transcriptome downstream of TAL-1 or LYL1 in human endothelial cells reveals that they modulate the same set of genes as well as distinct genes, suggesting that the two factors occupy distinct/complementary as well as redundant functions in endothelial cells.

Together, our data suggest a model, in which TAL-1 and LYL1 act in a coordinated manner during angiogenesis. While TAL-1 is required to initiate morphogenesis and development of the vascular tubes, LYL1 functions to stop this process and to promote the maturation of newly formed blood vessels. Our current model is depicted in the following figure:

The major aims of our current work are the followings:
- To validate at the molecular and functional levels signalization pathways downstream of TAL-1 and LYL1 (see figure).
- To dissociate hematopoietic and endothelial Lyl1 functions.
- To evaluate whether Lyl1 influences metastatic spreading.
- To extend the observations to endogenous tumor models.
- To evaluate the impact of Lyl1 and Tal-1 activity on pathological lymphangiogenesis.
- To investigate the impact of lyl1 on other vascular beds.


Institut de Génétique Moléculaire de Montpellier
CNRS-UMR 5535 - 1919, Route de Mende - 34293 Montpellier  Cedex 5
FRANCE
(+33) 04 34 35 96 01