Intraocular expression of endostatin reduces VEGF-induced retinal vascular permeability, neovascularization, and retinal detachment.
Endostatin, a proteolytic fragment of collagen XVIII, is an endogenous inhibitor of tumor angiogenesis that also inhibits choroidal neovascularization. In this study, we assessed the effects of increased intraocular expression of endostatin on vascular endothelial growth factor (VEGF)-induced changes in the retina. After subretinal injection of a pair of gutless adenoviral vectors (AGV) designed to provide tamoxifen-inducible expression of endostatin, diffuse endostatin immunoreactivity was induced thoroughout the retina by administration of tamoxifen. Induction of endostatin in double transgenic mice with doxycycline-induced expression of VEGF in the retina resulted in significant suppression of leakage of intravascular [3H]mannitol into the retina. The ability of endostatin to reduce VEGF-induced retinal vascular permeability was confirmed by using [3H]mannitol leakage and two other parameters, fluorescein leakage and retinal thickness, after subretinal injection of a bovine immunodeficiency lentiviral vector coding for endostatin (BIV-vectored endostatin, or BIVendostatin). Subretinal injection of BIVendostatin resulted in more discrete, less intense staining for endostatin in the retina than that seen with the inducible AGV system, which suggested lower levels and allowed visualization of sites where endostatin was concentrated. Endostatin staining outlined retinal blood vessels, which suggested endostatin binding to a component of vessel walls. More prolonged or higher level expression of VEGF in the retina resulted in neovascularization and retinal detachment, both of which were also significantly reduced by BIVendostatin. These data suggest that endostatin may be an endogenous inhibitor of vasopermeability as well as neovascularization. In patients with diabetic retinopathy, endostatin gene transfer may provide a way to decrease the risk of three causes of visual loss: macular edema, neovascularization, and retinal detachment.
Takahashi
Kyoichi
K
Department of Ophthalmology, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, Maryland 21287-9277, USA.
Saishin
Yoshitsugu
Y
Saishin
Yumiko
Y
Silva
Raquel Lima
RL
Oshima
Yuji
Y
Oshima
Sachiko
S
Melia
Michele
M
Paszkiet
Brian
B
Zerby
Dennis
D
Kadan
Michael J
MJ
Liau
Gene
G
Kaleko
Michael
M
Connelly
Sheila
S
Luo
Tianci
T
Campochiaro
Peter A
PA
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D043170:Collagen Type XVIII; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000235:genetics / Q000494:pharmacology*; D005123:Eye / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology*; D008222:Lymphokines / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012163:Retinal Detachment / Q000139:chemically induced / Q000473:pathology*; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000473:pathology*; D014162:Transfection / Q000379:methods; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D043170:Collagen Type XVIII; D043169:Endostatins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003094:Collagen