The mechanisms of laser-induced CNV and the imbalance of CNV developmentbetween the macula and extramacula are unclear. It has been proposed thata balance between factors that stimulate or inhibit vessel growth controlsneovascularization.26,27 In mostnormal tissues, inhibitory factors are active and vessels remain quiescent.26 In contrast, in different pathologic states, suchas tumor growth and neovascular forms of age-related macular degeneration,neovascularization occurs because of the disruption of the balance betweenangiogenic factors and angiogenic inhibitors.26- 28 Recentinvestigations have shown that sole overexpression of vascular endothelialgrowth factor, one of the most potent angiogenic growth factors, is sufficientto induce ocular neovascularization.22,29 Furthermore,vascular endothelial growth factor is involved in the maturation and stabilizationof newly formed vessels.28 With a disruptionof Bruch membrane, the effect of laser photocoagulation on the developmentof CNV is often attributed to the up-regulation of angiogenic factors. Previousstudies15,30- 32 havedemonstrated that expression of several angiogenic factors, including vascularendothelial growth factor, basic fibroblast growth factor, and matrix metalloproteinase2, is up-regulated in activated RPE and infiltrating cells in laser-inducedCNV. Most recently, Renno et al33 demonstratedthat down-regulation of pigment epithelium–derived factor, a potentendogenous inhibitor for vascular endothelial cell proliferation and migration,also enhances laser-induced CNV. In the normal retina, pigment epithelium–derivedfactor is expressed most intensely in the outer nuclear layer (photoreceptornuclei).33 After laser treatment, however,immunostaining for the factor within the outer nuclear layer was absent ordecreased for up to 3 weeks, which seemed to parallel the up-regulation ofvascular endothelial growth factor.15,30,31,33 Inthe present study, the macular region was predisposed to the incidence oflaser-induced CNV. Anatomically and physiologically, the macula is differentfrom the extramacula by its denser distribution of photoreceptors and RPEcells and more abundant blood supply from the choroidal circulation.34,35 It is possible that these differenceslead to the imbalance between the macula and extramacula in overexpressionof angiogenic factors and in down-regulation of angiogenic inhibitors afterlaser photocoagulation. Immunostaining for angiogenic factors and angiogenicinhibitors on macular and extramacular new vessels could clarify these speculations.However, all enucleated eyes in the present study were fixed in 2.5% glutaraldehydeplus 2% paraformaldehyde for a minimum of 24 hours, which challenges the immunostainingtechniques. Our study was initially designed to increase the incidence ofCNV in the primate model for preclinical evaluation of antiangiogenic therapies,rather than to investigate the mechanisms regulating CNV formation. When freshtissue is available in the future, further investigations will be directedto elucidate the molecular mechanisms that could explain the imbalance oflaser-induced CNV between the macular and extramacular regions.