Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity.
Retinopathy of prematurity is a blinding disease, initiated by lack of retinal vascular growth after premature birth. We show that lack of insulin-like growth factor I (IGF-I) in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor, important to vessel development. In vitro, low levels of IGF-I prevent vascular endothelial growth factor-induced activation of protein kinase B (Akt), a kinase critical for endothelial cell survival. Our results from studies in premature infants suggest that if the IGF-I level is sufficient after birth, normal vessel development occurs and retinopathy of prematurity does not develop. When IGF-I is persistently low, vessels cease to grow, maturing avascular retina becomes hypoxic and vascular endothelial growth factor accumulates in the vitreous. As IGF-I increases to a critical level, retinal neovascularization is triggered. These data indicate that serum IGF-I levels in premature infants can predict which infants will develop retinopathy of prematurity and further suggests that early restoration of IGF-I in premature infants to normal levels could prevent this disease.
Hellstrom
A
A
Department of Clinical Neuroscience, Section of Ophthalmology, and International Pediatric Growth Research Center, The Queen Silvia Children's Hospital, 41685 Göteborg, Sweden.
Perruzzi
C
C
Ju
M
M
Engstrom
E
E
Hard
A L
AL
Liu
J L
JL
Albertsson-Wikland
K
K
Carlsson
B
B
Niklasson
A
A
Sjodell
L
L
LeRoith
D
D
Senger
D R
DR
Smith
L E
LE
D001483:Base Sequence; D002470:Cell Survival; D017931:DNA Primers; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008222:Lymphokines / Q000378:metabolism*; D012171:Retinal Vessels / Q000166:cytology / Q000378:metabolism*; D012178:Retinopathy of Prematurity / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017931:DNA Primers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D007334:Insulin-Like Growth Factor I