Suppression and regression of choroidal neovascularization by systemic administration of an alpha5beta1 integrin antagonist.
Integrin alpha(5)beta(1) plays an important role in developmental angiogenesis, but its role in various types of pathologic neovascularization has not been completely defined. In this study, we found strong up-regulation of alpha(5)beta(1) in choroidal neovascularization. Implantation of an osmotic pump delivering 1.5 or 10 microg/h ( approximately 1.8 or 12 mg/kg/day) of 3-(2-{1-alkyl-5-[(pyridin-2-ylamino)-methyl]-pyrrolidin-3-yloxy}-acetylamino)-2-(alkylamino)-propionic acid (JSM6427), a selective alpha(5)beta(1) antagonist, caused significant suppression of choroidal neovascularization; the area of neovascularization was reduced by 33 to 40%. When an osmotic pump delivering 10 microg/h of JSM6427 was implanted 7 days after rupture of Bruch's membrane, there was terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining in vascular cells within the neovascularization and significant regression of the neovascularization over the next week. JSM6427 also induced apoptosis of cultured vascular endothelial cells. Fibronectin stimulates phosphorylation of extracellular signal-regulated kinase (ERK) in alpha(5)beta(1)-expressing cells that is blocked by JSM6427. These data suggest that alpha(5)beta(1) plays a role in the development and maintenance of choroidal neovascularization and provides a target for therapeutic intervention.
Umeda
Naoyasu
N
The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-9277, USA.
Kachi
Shu
S
Akiyama
Hideo
H
Zahn
Grit
G
Vossmeyer
Doerte
D
Stragies
Roland
R
Campochiaro
Peter A
PA
D000279:Administration, Cutaneous; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000631:Aminopyridines / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis; D001808:Blood Vessels / Q000737:chemistry / Q000166:cytology; D016570:Bruch Membrane / Q000033:anatomy & histology; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000295:instrumentation; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D015854:Up-Regulation; D014822:Vitreous Body / Q000033:anatomy & histology / Q000098:blood supply
D000631:Aminopyridines; D039081:Integrin alpha5beta1; D048049:Extracellular Signal-Regulated MAP Kinases; D000409:Alanine