LYL1 activity is required for the maturation of newly formed blood vessels in adulthood.
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.
Pirot
Nelly
N
Institut de Génétique Moléculaire de Montpellier, Unite Mixte de Recherche 5535, Centre Nationale de la Recherche Scientifique, Montpellier, France.
Deleuze
Virginie
V
El-Hajj
Rawan
R
Dohet
Christiane
C
Sablitzky
Fred
F
Couttet
Philippe
P
Mathieu
Danièle
D
Pinet
Valérie
V
D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015854:Up-Regulation / Q000235:genetics; D000099152:Cadherin 5
D042702:Angiopoietin-2; D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D000099152:Cadherin 5; C086541:LYL1 protein, human; C490130:Lyl1 protein, mouse; C489366:Tal1 protein, mouse