Recombinant non-collagenous domain of alpha2(IV) collagen causes involution of choroidal neovascularization by inducing apoptosis.
Vascular endothelial cells receive proangiogenic or antiangiogenic signals from components of extracellular matrix (ECM) depending upon the situation and many molecular signals can have opposite effects in different vascular beds. Tissue inhibitor of metalloproteinase 1 is antiangiogenic in several tissues, but promotes retinal neovascularization. When cleaved from native collagens, several of the non-collagenous domains (NC1) of basement membrane collagens have antiangiogenic effects in some tissues, but this is context dependent for the NC1 of the alpha 1 chain of collagen IV. It is critical to examine effects in several well-defined model systems before assuming that an ECM component is universally antiangiogenic. In this study, we examined the effects of a recombinant fragment of NC1 of the alpha 2 chain of type IV collagen (alpha2(IV)NC1) in a well-characterized model of ocular neovascularization. Intravitreous or periocular injections of alpha2(IV)NC1 caused selective apoptosis of endothelial cells participating in neovascularization resulting in suppression of neovascularization when the peptide was given prior to onset of new vessel sprouting. Importantly, when the peptide was given after neovascularization had already developed, it caused the new vessels to regress. This suggests that alpha2(IV)NC1, which has previously been shown to suppress tumor angiogenesis in xenograft models, is also a strong antiangiogenic agent in the choroid and is a therapeutic candidate for treatment of neovascular age-related macular degeneration.
The Department of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, Maumenee, Baltimore, Maryland 21287-9277, USA.
Raquel
R
Lima E Silva
Shu
S
Kachi
Hideo
H
Akiyama
Jikui
J
Shen
Sadia
S
Aslam
Yuan
Y
Yuan Gong
Naw Htee
NH
Khu
Maria C
MC
Hatara
Ariel
A
Boutaud
Robert
R
Peterson
Peter A
PA
Campochiaro
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002829:Choroid / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020256:Choroidal Neovascularization / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D024141:Collagen Type IV / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D020287:In Situ Nick-End Labeling; D007267:Injections; D007834:Lasers; D008268:Macular Degeneration / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D024141:Collagen Type IV; D011994:Recombinant Proteins