The heparan sulfate suleparoide inhibits rat corneal angiogenesis and in vitro neovascularization

被引:39
作者
Benelli, U
Bocci, G
Danesi, R
Lepri, A
Bernardini, N
Bianchi, F
Lupetti, M
Dolfi, A
Campagni, A
Agen, C
Nardi, M
Del Tacca, M
机构
[1] Univ Pisa, Dept Oncol, Div Pharmacol & Chemotherapy, I-56126 Pisa, Italy
[2] Univ Pisa, Dept Neurosci, Div Ophthalmol, I-56126 Pisa, Italy
[3] Univ Pisa, Dept Human Morphol & Appl Biol, I-56126 Pisa, Italy
[4] Scuola Super Sant Anna, Pisa, Italy
[5] Interforce Ctr Studies Mil Operat, CISAM, San Piero A Grado, Italy
关键词
angiogenesis; in vitro models; rat cornea; suleparoide; bFGF;
D O I
10.1006/exer.1998.0512
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
The purpose of this study was to evaluate the inhibitory activity of the heparan sulfate suleparoide on vascular cell growth in vitro and angiogenesis in vivo. Human HUV-EC-C endothelial cell proliferation and microvessel sprouting from cultured rat aortic rings were assayed by the bioreduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. The inhibition of the neoforming capillary network in the chorioallantoic membrane of chick embryo (CAM) was evaluated by agarose disks containing suleparoide and applied on the CAM surface. AgNO3/KNO3 injury was used to induce corneal neovascularization and to evaluate the therapeutic effect of topical suleparoide, while the involvement of bFGF in angiogenesis was evidenced by immunohistochemistry of corneal tissue. Quantitation of angiogenesis in the CAM and the cornea was accomplished by image analysis. Suleparoide dose-dependently inhibited HUV-EC-C cell proliferation (50% inhibitory concentration [IC50], 197.5 +/- 15.2 mu g ml(-1)) and reduced microvessel sprouting in vitro (IC50, 351 +/- 22 mu g ml(-1)). Likewise, suleparoide 150 mu g in agarose disks produced an avascular area of 19.7 +/- 2.7 % of the total area of the CAM (P < 0.05 as compared to controls). bFGF levels were significantly enhanced in the cornea after AgNO3/KNO3 injury, and the increase appeared to be time-dependent (25.6 +/- 1.8 and 43.2 +/- 7.4 %, vs. uninjured controls after 24 hr and 48 hr, respectively, P < 0.05). Suleparoide 4.8 mg eye(-1) day(-1) for six days reduced the length of blood vessels and the area of the cornea infiltrated by them (59.6 +/- 7.4% decrease vs. controls, P < 0.05). These results demonstrate that suleparoide is an active agent against angiogenesis and suggest that the therapeutic effect of the drug could be of value to treat corneal neovascularization. (C) 1998 Academic Press.
引用
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页码:133 / 142
页数:10
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