Endogenous endostatin inhibits choroidal neovascularization.
Endostatin, a fragment of the basement membrane component collagen XVIII, exhibits antiangiogenic properties in vitro and in vivo when high doses are administered. It is not known whether endogenous endostatin at physiological levels has a protective role as an inhibitor of pathological angiogenesis, such as choroidal neovascularization (CNV) in age-related macular degeneration. Using a laser injury model, we induced CNV in mice lacking collagen XVIII/endostatin and in control mice. CNV lesions in mutant mice were approximately 3-fold larger than in control mice and showed increased vascular leakage. These differences were independent of age-related changes at the choroid-retina interface. Ultrastructural analysis of the choroidal vasculature in mutant mice excluded morphological vascular abnormalities as a cause for the larger CNV lesions. When recombinant endostatin was administered to collagen XVIII/endostatin-deficient mice, CNV lesions were similar to those seen in control mice. In control mice treated with recombinant endostatin, CNV lesions were almost undetectable. These findings demonstrate that endogenous endostatin is an inhibitor of induced angiogenesis and that administration of endostatin potently inhibits CNV growth and vascular leakage. Endostatin may have a regulatory role in the pathogenesis of CNV and could be used therapeutically to inhibit growth and leakage of CNV lesions.
Marneros
Alexander G
AG
Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave., Boston, MA 02115, USA. alexander_marneros@yahoo.com
She
Haicheng
H
Zambarakji
Hadi
H
Hashizume
Hiroya
H
Connolly
Edward J
EJ
Kim
Ivana
I
Gragoudas
Evangelos S
ES
Miller
Joan W
JW
Olsen
Bjorn R
BR
D000818:Animals; D016570:Bruch Membrane / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002199:Capillary Permeability / Q000235:genetics / Q000502:physiology; D002829:Choroid / Q000098:blood supply / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D020256:Choroidal Neovascularization / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D043170:Collagen Type XVIII / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D043169:Endostatins / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D008268:Macular Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010843:Pichia / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage
D043170:Collagen Type XVIII; D043169:Endostatins; D005452:Fluoresceins; D008565:Membrane Proteins; D011994:Recombinant Proteins