Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease.
Retinal ischemia can cause vision-threatening pathological neovascularization. The mechanisms of retinal ischemia are not fully understood, however. Here we have shown that leukocytes prune the retinal vasculature during normal development and obliterate it in disease. Beginning at postnatal day 5 (P5) in the normal rat, vascular pruning began centrally and extended peripherally, leaving behind a less dense, smaller-caliber vasculature. The pruning was correlated with retinal vascular expression of intercellular adhesion molecule-1 (ICAM-1) and coincided with an outward-moving wave of adherent leukocytes composed in part of cytotoxic T lymphocytes. The leukocytes adhered to the vasculature through CD18 and remodeled it through Fas ligand (FasL)-mediated endothelial cell apoptosis. In a model of oxygen-induced ischemic retinopathy, this process was exaggerated. Leukocytes used CD18 and FasL to obliterate the retinal vasculature, leaving behind large areas of ischemic retina. In vitro, T lymphocytes isolated from oxygen-exposed neonates induced a FasL-mediated apoptosis of hyperoxygenated endothelial cells. Targeting these pathways may prove useful in the treatment of retinal ischemia, a leading cause of vision loss and blindness.
Ishida
Susumu
S
Angiogenesis/Retina Research Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, 325 Cambridge Street, Boston, Massachusetts 02114, USA.
Yamashiro
Kenji
K
Usui
Tomohiko
T
Kaji
Yuichi
Y
Ogura
Yuichiro
Y
Hida
Tetsuo
T
Honda
Yoshihito
Y
Oguchi
Yoshihisa
Y
Adamis
Anthony P
AP
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism; D018801:CD2 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D012160:Retina / Q000473:pathology; D012164:Retinal Diseases / Q000378:metabolism / Q000473:pathology*; D015861:Retinal Neovascularization; D012171:Retinal Vessels / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology*
D018952:Antigens, CD34; D018821:CD18 Antigens; D018801:CD2 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D018799:Intercellular Adhesion Molecule-1; D017493:Leukocyte Common Antigens