The process of CNV formation starts with the growth of blood vessels from the choroid, which then extends through the Bruch membrane under the RPE (sub-RPE CNV) (21). The CNV may then extend further into the subretinal space (22). This abnormal neovascular process leads to serous or hemorrhagic detachment of the RPE and/or neurosensory retina. Eventually, if untreated, scarring will ensue and degeneration of photoreceptors and RPE and subsequent loss of central vision will occur (23).

The signals that stimulate the invasion of choroidal vessels through Bruch’s membrane are not completely understood. Under normal circumstances the RPE secretes VEGF at its basolateral surface, which helps to maintain the fenestrations in the choriocapillaris (24). With aging, accumulation of lipofuscin in the RPE and deposition of material (predominantly lipid) and subsequent thickening in Bruch’s membrane occurs (25,26). These events result in reduced oxygen transmission from the choriocapillaris into the outer retina with outer retinal hypoxia and subsequent upregulation of VEGF secretion by the RPE (27), which could lead to CNV formation. It is thought that the neovascular complex in these cases provides nutrients and oxygen to the ischemic RPE/outer retina, which is expressing VEGF (28,29). Activated macrophages may migrate from the choroid into Bruch’s membrane with the goal of removing the waste material deposited in this layer, with the possible creation of channels in Bruch’s membrane through which blood vessels could then invade the retina (30). It has been shown that the RPE can produce monocyte-chemoattractant-protein and IL8 during the active phase of CNV development, which would stimulate the migration of monocytes (macrophages) from the choriocapillaris into the outer surface of Bruch membrane (31). Macrophages obtained from surgically removed CNVs and from whole postmortem eyes with CNV showed increased expression of many inflammatory cytokines by these cells (31). Increased expression of many growth factors, specifically VEGF, in the RPE and photoreceptors, as well as recruited macrophages and proliferation of vascular endothelium from choriocapillaris, has been demonstrated in specimens obtained from patients with neovascular AMD (28,29,31,32).

Gass (33) suggested that CNV in AMD grows predominantly under the RPE (so-called type 1 CNV), although in some patients it can extend mainly into the subretinal space (type 2 CNV). Several histopathology studies have shown that in CNVs angiographically classified as occult, the growth of new vessels occurred predominantly underneath the RPE (22,34, 35, 36, 37, 38). In contrast, lesions classified angiographically as classic CNVs contained a subretinal neovascular component, with or without a sub-RPE component (22,34). A combination of both types has also been found (39). CNVs are classified as classic on fluorescein angiography (FA) when they demonstrate early, well-defined hyperfluorescence and late leakage blurring the margins, and as occult when ill-defined, late, stippled hyperfluorescence or late leakage of undetermined source is present (2).

Histopathology studies of surgically excised RAP lesions showed an intraretinal neovascular mass in all cases; in some specimens, an additional CNV was also found (40,41). Immunohistochemistry in these cases demonstrated expression of hypoxiainduced growth factors and macrophages, suggesting that ischemia and inflammation may be involved in the pathogenesis of RAP (41). Histopathology studies in enucleated eyes of patients with IPCV showed large, thin-walled choroidal vessels underneath the RPE with choroidal capillary proliferation (42,43).