Inhibition of platelet-derived growth factor promotes pericyte loss and angiogenesis in ischemic retinopathy.
We investigated whether inhibition of platelet-derived growth factor (PDGF) receptor tyrosine kinase activity would affect pericyte viability, vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR-2) expression and angiogenesis in a model of retinopathy of prematurity (ROP). ROP was induced in Sprague Dawley rats by exposure to 80% oxygen from postnatal (P) days 0 to 11 (with 3 hours/day in room air), and then room air from P12-18 (angiogenesis period). Shams were neonatal rats in room air from P0-18. STI571, a potent inhibitor of PDGF receptor tyrosine kinase, was administered from P12-18 at 50 or 100 mg/kg/day intraperitoneal (i.p.). Electron microscopy revealed that pericytes in the inner retina of both sham and ROP rats appeared normal; however STI571 induced a selective pericyte and vascular smooth muscle degeneration. Immunolabeling for caspase-3 and alpha-smooth muscle cell actin in consecutive paraffin sections of retinas confirmed that these degenerating cells were apoptotic pericytes. In all groups, VEGF and VEGFR-2 gene expression was located in ganglion cells, the inner nuclear layer, and retinal pigment epithelium. ROP was associated with an increase in both VEGF and VEGFR-2 gene expression and blood vessel profiles in the inner retina compared to sham rats. STI571 at both doses increased VEGF and VEGFR-2 mRNA and exacerbated angiogenesis in ROP rats, and in sham rats at 100 mg/kg/day. In conclusion, PDGF is required for pericyte viability and the subsequent prevention of VEGF/VEGFR-2 overexpression and angiogenesis in ROP.
Wilkinson-Berka
Jennifer L
JL
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia. jlaberka@unimelb.edu.au
Babic
Sanja
S
De Gooyer
Tanyth
T
Stitt
Alan W
AW
Jaworski
Kassie
K
Ong
Leslie G T
LG
Kelly
Darren J
DJ
Gilbert
Richard E
RE
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007231:Infant, Newborn; D008854:Microscopy, Electron; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009389:Neovascularization, Pathologic / Q000473:pathology*; D020286:Pericytes / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D010982:Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012160:Retina / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D012171:Retinal Vessels / Q000502:physiology; D012178:Retinopathy of Prematurity / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D020794:Receptor Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2