Different effects of angiopoietin-2 in different vascular beds: new vessels are most sensitive.
In this study, we used double transgenic mice with inducible expression of angiopoietin-2 (Ang2) to investigate the role of Ang2 in the retinal and choroidal circulations and in three models of ocular neovascularization (NV). Mice with induced expression of Ang2 ubiquitously, or specifically in the retina, survived and appeared grossly normal. They also had normal-appearing retinal and choroidal circulations, demonstrating that high levels of Ang2 did not induce regression of mature retinal or choroidal vessels. When Ang2 expression was induced soon after birth, there was increased density of the deep capillary bed on postnatal day (P) 11 that returned to normal by P18, the time that retinal vascular development is usually completed. In mice with ischemic retinopathy, induction of Ang2 during the ischemic period resulted in a significant increase in retinal NV, but induction of Ang2 at a later time point when ischemia (and vascular endothelial growth factor [VEGF]) was less, hastened regression of NV. In triple transgenic mice that coexpressed VEGF and Ang2, the increased expression of Ang2 inhibited VEGF-induced NV in the retina. Increased expression of Ang2 also resulted in regression of choroidal neovascularization. These data suggest that ocular neovascularization, but not mature retinal or choroidal vessels, is sensitive to Ang2; a high Ang2/VEGF ratio promotes regression, while high Ang2 in the setting of hypoxia and/or concomitantly high Ang2 and VEGF stimulate neovascularization.
Oshima
Yuji
Y
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Oshima
Sachiko
S
Nambu
Hiroyuki
H
Kachi
Shu
S
Takahashi
Kyoichi
K
Umeda
Naoyasu
N
Shen
JiKui
J
Dong
Aling
A
Apte
Rajendra S
RS
Duh
Elia
E
Hackett
Sean F
SF
Okoye
Godwin
G
Ishibashi
Kazuki
K
Handa
James
J
Melia
Michele
M
Wiegand
Stanley
S
Yancopoulos
George
G
Zack
Donald J
DJ
Campochiaro
Peter A
PA
D042702:Angiopoietin-2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000254:growth & development*; D002196:Capillaries / Q000254:growth & development; D002829:Choroid / Q000098:blood supply; D004318:Doxycycline / Q000008:administration & dosage; D015870:Gene Expression; D007511:Ischemia / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010786:Photoreceptor Cells / Q000737:chemistry; D012333:RNA, Messenger / Q000032:analysis; D012160:Retina / Q000737:chemistry; D012171:Retinal Vessels / Q000254:growth & development / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012243:Rhodopsin / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology / Q000502:physiology
D042702:Angiopoietin-2; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D012243:Rhodopsin; D004318:Doxycycline