Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor

Aberrant blood vessel growth in the retina that underlies the pathology of proliferative diabetic retinopathy and retinopathy of prematurity is the re sult of the ischemia-driven disruption of the normally antiangiogenic envir onment of the retina, In this study, we show that a potent inhibitor of ang iogenesis found naturally in the normal eye, pigment epithelium-derived gro wth factor (PEDF), inhibits such aberrant blood vessel growth in a murine m odel of ischemia-induced retinopathy, Inhibition was proportional to dose a nd systemic delivery of recombinant protein at daily doses as low as 2.2 mg /kg could prevent aberrant endothelial cells from crossing the inner limiti ng membrane. PEDF appeared to inhibit angiogenesis by causing apoptosis of activated endothelial cells, because it induced apoptosis in cultured endot helial cells and an 8-fold increase in apoptotic endothelial cells could be detected in situ when the ischemic retinas of PEDF-treated animals were co mpared with vehicle-treated controls. The ability of low doses of PEDF to c urtail aberrant growth of ocular endothelial cells without overt harm to re tinal morphology suggests that this natural protein may be beneficial in th e treatment of a variety of retinal vasculopathies.