A heparin mimetic isolated from a marine shrimp suppresses neovascularization.
BACKGROUND
Choroidal neovascularization (CNV) is the main cause of severe visual loss in age-related macular degeneration (AMD). Heparin/heparan sulfate are known to play important roles in neovascularization due to their abilities to bind and modulate angiogenic growth factors and cytokines. Previously, we have isolated from marine shrimp a heparin-like compound with striking anti-inflammatory action and negligible anticoagulant and hemorrhagic activities.


OBJECTIVE
To investigate the role of this novel heparin-like compound in angiogenic processes.


RESULTS
The anti-angiogenic effect of this heparinoid in laser-induced CNV and in vitro models is reported. The compound binds to growth factors (FGF-2, EGF and VEGF), blocks endothelial cell proliferation and shows no cytotoxic effect. The decrease in proliferation is not related to cell death either by apoptosis or secondary necrosis. The results also showed that the heparinoid modified the 2-D network organization in capillary-like structures of endothelial cells in Matrigel and reduced the CNV area. The effect on CNV area correlates with decreases in the levels of VEGF and TGF-β1 in the choroidal tissue. The low content of 2-O-sulfate groups in this heparinoid may explain its potent anti-angiogenic effect.


CONCLUSIONS
The properties of the shrimp heparinoid, such as potent anti-angiogenic and anti-inflammatory activities but insignificant anticoagulant or hemorrhagic actions, point to this compound as a compelling drug candidate for treating neovascular AMD and other angioproliferative diseases. A mechanism for the anti-angiogenic effect of the heparinoid is proposed.
Dreyfuss
J L
JL
Departmento de Bioquímica, Disciplina de Biologia Molecular, Universidade Federal de São Paulo, Brazil.
Regatieri
C V
CV
Lima
M A
MA
Paredes-Gamero
E J
EJ
Brito
A S
AS
Chavante
S F
SF
Belfort
R
R
Farah
M E
ME
Nader
H B
HB
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D020256:Choroidal Neovascularization; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D006025:Glycosaminoglycans / Q000737:chemistry; D006493:Heparin / Q000737:chemistry*; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin / Q000737:chemistry; D009389:Neovascularization, Pathologic; D033561:Penaeidae; D011509:Proteoglycans / Q000737:chemistry; D051381:Rats; D011924:Rats, Zucker
D004338:Drug Combinations; D006025:Glycosaminoglycans; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D006493:Heparin; D003094:Collagen