Synthetic peptides interacting with the 67-kd laminin receptor can reduce retinal ischemia and inhibit hypoxia-induced retinal neovascularization.
The high-affinity 67-kd laminin receptor (67LR) is expressed by proliferating endothelial cells during retinal neovascularization. The role of 67LR has been further examined experimentally by administration of selective 67LR agonists and antagonists in a murine model of proliferative retinopathy. These synthetic 67LR ligands have been previously shown to stimulate or inhibit endothelial cell motility in vitro without any direct effect on proliferation. In the present study, a fluorescently labeled 67LR antagonist (EGF(33-42)) was injected intraperitoneally into mice and its distribution in the retina was assessed by confocal scanning laser microscopy. Within 2 hours this peptide was localized to the retinal vasculature, including preretinal neovascular complexes, and a significant amount had crossed the blood retinal barrier. For up to 24 hours postinjection, the peptide was still present in the retinal vascular walls and, to a lesser extent, in the neural retina. Non-labeled EGF(33-42) significantly inhibited pre-retinal neovascularization in comparison to controls treated with phosphate-buffered saline or scrambled peptide (P < 0.0001). The agonist peptide (Lam beta 1(925-933)) also significantly inhibited proliferative retinopathy; however, it caused a concomitant reduction in retinal ischemia in this model by promoting significant revascularization of the central retina (P < 0.001). Thus, 67LR appears to be an important target receptor for the modulation of retinal neovascularization. Agonism of this receptor may be valuable in reducing the hypoxia-stimulated release of angiogenic growth factors which drives retinal angiogenesis.
Gebarowska
Dorota
D
Centre of Ophthalmology and Vision Science and the School of Biology and Biochemistry, The Queen's University of Belfast, Royal Victoria Hospital, Belfast, Northern Ireland, United Kingdom.
Stitt
Alan W
AW
Gardiner
Thomas A
TA
Harriott
Patrick
P
Greer
Brett
B
Nelson
John
J
D000818:Animals; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000627:therapeutic use*; D000860:Hypoxia / Q000188:drug therapy*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D007797:Laminin / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010446:Peptide Fragments / Q000378:metabolism / Q000627:therapeutic use*; D017474:Receptors, Laminin / Q000737:chemistry / Q000502:physiology*; D012164:Retinal Diseases / Q000473:pathology / Q000503:physiopathology*; D012171:Retinal Vessels / Q000187:drug effects*
D007797:Laminin; D010446:Peptide Fragments; D017474:Receptors, Laminin; C101875:epidermal growth factor (33-42); C459079:laminin beta1 (925-933); D004815:Epidermal Growth Factor