Reduced retinal angiogenesis in MMP-2-deficient mice.
OBJECTIVE
To study the putative role of endogenous matrix metalloproteinases (MMPs) in retinal neovascularization, an established mouse model was used to compare the retinal neovascularization observed in wild-type mice with that in mice without the MMP-2 or -9 genes.


METHODS
C57Bl/6 (MMP-2(+/+) and -9(+/+)), MMP-2-deficient (MMP-2(-/-)), and MMP-9-deficient (MMP-9(-/-)) mice were used. After oxygen-induced retinopathy was induced in the mice, their eyes were rapidly removed and frozen in optimal cutting temperature embedding compound. Sections were histochemically stained with specific markers for vascular cells and angiogenesis-related factors. The area of new retinal vessels was measured using image-analysis software and compared between groups.


RESULTS
Retinal neovascularization was not significantly different between wild-type and MMP-9(-/-) mice. The MMP-2(-/-) mice had significantly less extraretinal neovascularization than did wild-type mice. The mean number of extraretinal neovascular buds per cross section was significantly lower in MMP-2(-/-) mice than in wild-type mice (P < 0.05). The expression of other angiogenesis-related factors, vascular endothelial growth factor and pigment epithelium-derived factor, was not different between wild-type and MMP-2(-/-) mice.


CONCLUSIONS
MMP-2 may be essential in the regulation of retinal neovascularization. Pharmacologic intervention using MMP inhibitors may be a future therapeutic approach for angiogenic retinal diseases.
Ohno-Matsui
Kyoko
K
Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan. k.ohno.oph@med.tmd.ac.jp
Uetama
Tomoko
T
Yoshida
Takeshi
T
Hayano
Masato
M
Itoh
Takeshi
T
Morita
Ikuo
I
Mochizuki
Manabu
M
D000818:Animals; D000831:Animals, Newborn; D003911:Dextrans; D004195:Disease Models, Animal; D005136:Eye Proteins; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives*; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors; D011506:Proteins / Q000378:metabolism; D015861:Retinal Neovascularization / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012178:Retinopathy of Prematurity / Q000150:complications; D015843:Serpins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D003911:Dextrans; D005136:Eye Proteins; D016650:Fluorescein-5-isothiocyanate; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009414:Nerve Growth Factors; D011506:Proteins; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C015219:fluorescein isothiocyanate dextran