Angiopoietins contribute to lung development by regulating pulmonary vascular network formation.
Angiopoietin (Ang) signaling through the Tie2 receptor regulates vasculature. The role of Ang signaling in pulmonary hypertension is well investigated, but its role in lung development is not elucidated. Here, we show that the Tie2 agonist ligand, Ang1, was detected in lung tissue at birth and its expression gradually increased in mice, whereas its antagonist Ang2 was abundant at birth and decreased inversely with Ang1. Mice expressing the potent chimeric Ang1 protein COMP-Ang1 in surfactant protein C (SPC)-positive lung epithelial cells, showed 50% lethality at birth due to respiratory failure. Surviving mice displayed impaired adaptive responsive respiratory function. Histological analysis revealed that pulmonary artery and alveolar structure were significantly dilated, and alveolar density was decreased to approximately a third of controls. Thus, the precise regulation of Tie2 signaling through an Ang1/Ang2 expression switch is important to construct a mature lung vascular network system required for normal lung development.
Hato
Tai
T
Department of Cell Differentiation, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8556, Japan.
Kimura
Yoshishige
Y
Morisada
Tohru
T
Koh
Gou Young
GY
Miyata
Keishi
K
Tabata
Mitsuhisa
M
Kadomatsu
Tsuyoshi
T
Endo
Motoyoshi
M
Urano
Takashi
T
Arai
Fumio
F
Araki
Kimi
K
Suda
Toshio
T
Kobayashi
Koichi
K
Oike
Yuichi
Y
D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000002:abnormalities / Q000098:blood supply* / Q000254:growth & development*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics*; D042787:Receptor, TIE-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014664:Vasodilation / Q000235:genetics
D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; C515576:COMP-Ang1 fusion protein; D011993:Recombinant Fusion Proteins; D042787:Receptor, TIE-2