Endogenous endostatin inhibits choroidal neovascularization

Abstract

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.

Gene Therapies for Neovascular Age-Related Macular Degeneration

“…A role for endogenous endostatin in inhibiting experimental CNV has also been shown (Marneros et al 2007). Intravenous (tail vein) injection of Adendostatin under control of the CMV or Rous sarcoma virus promoter also completely prevented CNV development in a laser-induced mouse model of CNV (Mori et al 2001b).…”

Quantification of Optical In-Vivo Imaging of Retinal and Choroidal Neovascularization and Cell Migration in the Mouse Fundus

“…Choroidal neovascularisation (CNV) is a complication that occurs for instance in an advanced stage of age-related macular degeneration ("wet" AMD), initially inducing a local inflammation [6][7][8]. In order to study various aspects of CNV, the experimental model of laser-induced CNV is frequently used.…”

“…In contrast to AF, in fluorescence angiography (FA) a fluorescent dye is injected into the systemic blood circulation, therefore allowing visualisation of blood vessels [12]. As an example, quantification of vessel leakage in laser-induced CNV has been performed using a grading system, in which two independent observers assigned fluorescence intensities to four stages of hyperfluorescence in comparison to a study-individual control [7]. Such quantifications are not objective and not applicable in conditions where changes are not very obvious.…”

Regulation of Angiogenesis in Choroidal Neovascularization of Age Related Macular Degeneration by Endogenous Angioinhibitors

“…Lower levels of endostatin have been recorded in CNV samples compared to the healthy donor eyes and within the tissues of progressive AMD (Bhutto et al, 2008;Fukai et al, 2002). Deletion of endostatin or collagen type XVIII massively up-regulates LASER induced CNV; where as administration of physiological concentrations of endostatin was able to inhibit such CNV in these mice (Marneros et al, 2007). Endostatin also down regulates the expression of VEGF in experimental CNV rat models (Takahashi et al, 2003).…”