A subretinal matrigel rat choroidal neovascularization (CNV) model and inhibition of CNV and associated inflammation and fibrosis by VEGF trap.
OBJECTIVE
The exudative, or the wet form of age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). A subretinal Matrigel (BD Biosciences, Bedford MA) model of CNV is described here, along with the effects of vascular endothelial growth factor (VEGF) neutralization on the development of CNV and associated inflammation and fibrosis.


METHODS
CNV was induced in adult Sprague-Dawley rats by subretinal injection of Matrigel. CNV growth and associated leukocyte infiltration and collagen deposition were examined. VEGF Trap (Regeneron Pharmaceuticals, Tarrytown, NY), a recombinant protein that comprises portions of the extracellular domains of VEGF receptors 1 and 2 and that binds all isoforms of VEGF-A as well as placental growth factor with high affinity, was administered subcutaneously.


RESULTS
Initiation of CNV was detected 4 days after Matrigel injection and then increased progressively in size. Systemic administration of VEGF Trap beginning on day 2 and 6 completely prevented development of CNV. When CNV was allowed to develop for 10 days before treatment was initiated, VEGF Trap not only prevented its further progression, but also induced substantial regression of existing lesions. In addition, VEGF Trap treatment reduced the total lesion volume and largely prevented the progressive leukocyte infiltration and fibrosis associated with CNV.


CONCLUSIONS
The subretinal Matrigel CNV model provides a convenient tool for the study of the diverse components of complex CNV lesions. The data not only confirm the critical roles of VEGF in the development and maintenance of CNV, but further demonstrate that VEGF and other VEGF receptor 1 ligands promote CNV-associated inflammation and fibrosis.
Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA.
Jingtai
J
Cao
Lian
L
Zhao
Yiwen
Y
Li
Yang
Y
Liu
Weihong
W
Xiao
Ying
Y
Song
Lingyu
L
Luo
Deqiang
D
Huang
George D
GD
Yancopoulos
Stanley J
SJ
Wiegand
Rong
R
Wen
D000199:Actins / Q000378:metabolism; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002833:Choroiditis / Q000517:prevention & control*; D003094:Collagen / Q000378:metabolism / Q000633:toxicity*; D004195:Disease Models, Animal; D004338:Drug Combinations; D005355:Fibrosis / Q000517:prevention & control; D007279:Injections, Subcutaneous; D007797:Laminin / Q000633:toxicity*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D018613:Microscopy, Confocal; D011509:Proteoglycans / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism
D000199:Actins; D003094:Collagen; D004338:Drug Combinations; D007797:Laminin; D017493:Leukocyte Common Antigens; D011509:Proteoglycans; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D014746:Vimentin; C498862:Acta2 protein, rat; C467498:vascular endothelial growth factor A, rat; C059485:matrigel; C533178:aflibercept