Kinetics of integrin expression in the mouse model of proliferative retinopathy and success of secondary intervention with cyclic RGD peptides.
OBJECTIVE
Vitronectin-receptor-type integrins (alpha(v) beta(3) and alpha(v) beta(5)) are thought to be involved in the selective ablation of tumorigenic and other pathologic angiogenesis. Specifically, it has been shown that ligation inhibition of the alpha(v)-type integrins with cyclic penta-peptid peptide inhibits proliferative retinopathy by almost 80 % in a hypoxia-induced mouse model.


METHODS
On the basis of growth factor and integrin expression dynamics in this model, secondary intervention approaches with cyclic RGDfV peptide were investigated.


RESULTS
alpha(v)-integrin expression started immediately after induction of hypoxia (at postnatal day 12, p12) and persisted only during the initial period of neovascularization (until day p14). Vascular endothelial growth factor (VEGF) expression started at high values immediately after return of the mice into room air, and dropped rapidly to low values beyond day 13. In contrast, basic fibroblast growth factor (bFGF) was predominantly expressed during the phase of maximum angiogenesis which was noted between day p17 and 19. Based on these findings, cyclic penta peptide was administered subcutaneously at varying doses (2-20 microg/kg/day) for 5 days beginning either at day p14 (early intervention) or at day p17 (late intervention). Early secondary intervention showed a dose-dependent reduction of new vessels with maximum inhibition of 57 % (control 68.08 +/- 3.21 nuclei/section compared with RGDfV-treated 29.35 +/- 2.39 nuclei/section; p < 0.0001), whereas late secondary intervention had no effect.


CONCLUSIONS
These data indicate that angiogenesis-related alpha(v)-integrin expression is VEGF- rather than bFGF-dependent, and the efficacy of cyclic penta-peptid (RGDfV)-treatment in proliferative retinopathy is only effective as long as the alpha(v)-integrin target is prominently expressed.
Chavakis
E
E
III Medical Department, Justus-Liebig-University, Giessen, Germany.
Riecke
B
B
Lin
J
J
Linn
T
T
Bretzel
R G
RG
Preissner
K T
KT
Brownlee
M
M
Hammes
H-P
HP
D000818:Animals; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000276:immunology*; D004195:Disease Models, Animal; D016023:Integrins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D012171:Retinal Vessels / Q000473:pathology
D016023:Integrins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; C047981:arginyl-glycyl-aspartic acid