Spontaneous corneal hem- and lymphangiogenesis in mice with destrin-mutation depend on VEGFR3 signaling.
Lymphangiogenesis, the formation of new lymphatic vessels, is important for tumor metastasis and induction of immunity to peripheral antigens including organ transplants. We herein describe a novel mouse model of spontaneous, secondary lymphangiogenesis in the normally avascular cornea. corn1 mice, which suffer from a deletion in the gene encoding the cytoskeletal protein destrin, develop hemangiogenesis as well as spontaneous outgrowth of LYVE-1+++/CD31+ lymphatic vessels into the cornea starting at age 4 weeks. Corneal lymphangiogenesis is delayed in onset, is less intense, and regresses earlier compared with hemangiogenesis. Moreover, the lymphangiogenesis is preceded only by a mild recruitment of CD45+ inflammatory cells into the cornea. In contrast to mice with inflammation-induced hem- and lymphangiogenesis, corn1 mice do not develop breakdown of the blood-aqueous barrier. Finally, in this novel mouse model, a blocking anti-VEGFR3 antibody significantly inhibited not only lymph- but also hemangiogenesis. In summary, destrin deletion has differential effects on spontaneous hem- and lymphangiogenesis in the normally avascular cornea and represents a novel mouse model to study the mechanisms of lymphangiogenesis and to test the antihem- and antilymphangiogenic properties of known or new antiangiogenic agents.
Cursiefen
Claus
C
Department of Ophthalmology, Friedrich-Alexander-University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany. cursiefen@vision.eri.harvard.edu
Ikeda
Sakae
S
Nishina
Patsy M
PM
Smith
Richard S
RS
Ikeda
Akihiro
A
Jackson
David
D
Mo
Jun-Song
JS
Chen
Lu
L
Dana
M Reza
MR
Pytowski
Bronislaw
B
Kruse
Friedrich E
FE
Streilein
J Wayne
JW
D051339:Actin Depolymerizing Factors; D000818:Animals; D001082:Aqueous Humor / Q000166:cytology / Q000378:metabolism; D003315:Cornea / Q000098:blood supply / Q000502:physiology*; D051345:Destrin; D005136:Eye Proteins / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics; D007958:Leukocyte Count; D016850:Limbus Corneae / Q000378:metabolism; D042583:Lymphangiogenesis / Q000502:physiology*; D008208:Lymphatic System / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics*; D009154:Mutation; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
D051339:Actin Depolymerizing Factors; D051345:Destrin; C495825:Dstn protein, mouse; D005136:Eye Proteins; D006133:Growth Substances; D008840:Microfilament Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040321:Vascular Endothelial Growth Factor Receptor-3