Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation.
Angiopoietin (Ang) signaling plays a role in angiogenesis and remodeling of blood vessels through the receptor tyrosine kinase Tie2, which is expressed on blood vessel endothelial cells (BECs). Recently it has been shown that Ang-2 is crucial for the formation of lymphatic vasculature and that defects in lymphangiogenesis seen in Ang-2 mutant mice are rescued by Ang-1. These findings suggest important roles for Ang signaling in the lymphatic vessel system; however, Ang function in lymphangiogenesis has not been characterized. In this study, we reveal that lymphatic vascular endothelial hyaluronan receptor 1-positive (LYVE-1(+)) lymphatic endothelial cells (LECs) express Tie2 in both embryonic and adult settings, indicating that Ang signaling occurs in lymphatic vessels. Therefore, we examined whether Ang-1 acts on in vivo lymphatic angiogenesis and in vitro growth of LECs. A chimeric form of Ang-1, cartilage oligomeric matrix protein (COMP)-Ang-1, promotes in vivo lymphatic angiogenesis in mouse cornea. Moreover, we found that COMP-Ang-1 stimulates in vitro colony formation of LECs. These Ang-1-induced in vivo and in vitro effects on LECs were suppressed by soluble Tie2-Fc fusion protein, which acts as an inhibitor by sequestering Ang-1. On the basis of these observations, we propose that Ang signaling regulates lymphatic vessel formation through Tie2.
Morisada
Tohru
T
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan.
Oike
Yuichi
Y
Yamada
Yoshihiro
Y
Urano
Takashi
T
Akao
Masaki
M
Kubota
Yoshiaki
Y
Maekawa
Hiromitsu
H
Kimura
Yoshishige
Y
Ohmura
Masako
M
Miyamoto
Takeshi
T
Nozawa
Shiro
S
Koh
Gou Young
GY
Alitalo
Kari
K
Suda
Toshio
T
D042683:Angiopoietin-1 / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006023:Glycoproteins / Q000096:biosynthesis*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D007763:Lac Operon; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D009154:Mutation; D042787:Receptor, TIE-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection
D042683:Angiopoietin-1; D000911:Antibodies, Monoclonal; D006023:Glycoproteins; D049452:Green Fluorescent Proteins; D018960:Hyaluronan Receptors; D026901:Membrane Transport Proteins; D042787:Receptor, TIE-2; D011993:Recombinant Fusion Proteins; C492273:LYVE1 protein, mouse