Decreased hypoxia-induced neovascularization in angiopoietin-2 heterozygous knockout mouse through reduced MMP activity.
OBJECTIVE
Proliferative diabetic retinopathy is characterized by the formation of retinal neovascularization. Angiopoietin-2 (Ang-2) and matrix metalloproteinase (MMP) play a critical role in angiogenesis. However, the precise location and function of Ang-2 during formation of retinal neovascularizations driven by hypoxia in relation to MMP activity have not been elucidated. In this study, we investigated the response of Ang-2 heterozygous knockout retinas (Ang2(+/-) mouse) to hypoxia and its link to MMP activity in an oxygen-induced retinopathy (OIR) model.


METHODS
Pre-retinal neovascularizations were quantitated in vertical sections. Intra-retinal angiogenesis was assessed by whole mount immunofluorescence staining of retinas. MMP activity was examined in retinal protein lysate and whole mount retinal in situ zymography.


RESULTS
Ang2(+/-) retinas subjected to the OIR model showed 33% reduced neovascularization and 271% increased avascular zones at postnatal day 17. In the OIR model, Ang-2 was modestly expressed in pre-retinal neovascularizations and venules, but strongly in arterioles and capillary sprouts. MMPs were activated in close association to where Ang-2 is expressed. MMP activity was substantially decreased in Ang2(+/-) retinas.


CONCLUSIONS
Our present data suggest the spatially concomitant expression of Ang2 and MMPs, and that Ang2 modulates hypoxia-induced neovascularization by regulating MMP activity.
Feng
Yuxi
Y
5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Wang
Yumei
Y
Pfister
Frederick
F
Hillebrands
Jan-Luuk
JL
Deutsch
Urban
U
Hammes
Hans-Peter
HP
D042702:Angiopoietin-2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000860:Hypoxia / Q000150:complications*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D012160:Retina / Q000473:pathology; D015861:Retinal Neovascularization / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism
D042702:Angiopoietin-2; D020782:Matrix Metalloproteinases