Clinical and experimental observations indicate a role for VEGF secreted by the retinal pigment epithelium (RPE) in the maintenance of the choriocapillaris (CC). VEGF in mice is produced as three isoforms, VEGF120, VEGF164, and VEGF188, that differ in their ability to bind heparan sulfate proteoglycan. RPE normally produces the more soluble isoforms, VEGF120 and VEGF164, but virtually no VEGF188, reflecting the fact that molecules secreted by the RPE must diffuse across Bruch's membrane (BrM) to reach the choriocapillaris. To determine the role of RPE-derived soluble VEGF on the choriocapillaris survival, we used mice that produce only VEGF188. VEGF188/188 mice exhibited normal choriocapillaris development. However, beginning at 7 months of age, we observed a progressive degeneration characterized by choriocapillaris atrophy, RPE and BrM abnormalities, culminating in areas of RPE loss and dramatic choroidal remodeling. Increased photoreceptor apoptosis in aged VEGF188/188 mice led to a decline in visual acuity as detected by electroretinogram (ERG). These changes are reminiscent of geographic atrophy (GA) and point to a role for RPE-derived VEGF in the maintenance of the choriocapillaris.age-related macular degeneration ͉ Bruch's membrane ͉ geographic atrophy ͉ retinal pigmented epithelium

Although vascular endothelial growth factor (VEGF) has been well studied in both developmental and pathological angiogenesis, its role in mature blood vessels is poorly understood. A growing body of observations, including the side effects of anti-VEGF therapies as well as the role of soluble VEGFR1 in preeclampsia, points to an important role for VEGF in maintenance of stable blood vessels. To better understand the potential function of VEGF in mature vessels, a survey of VEGF localization in adult mice was conducted. In adult VEGF-lacZ mice, VEGF was expressed in a cell-specific manner by cells overlying fenestrated and sinusoidal blood vessels, including podocytes, choroid plexus epithelium, and hepatocytes, as well as in tissues with high metabolic demands or with secretory functions, such as cardiac and skeletal myocytes, Leydig cells, prostatic epithelium, and salivary serous epithelium. VEGF was not detected in most endothelium but was specifically expressed by aortic endothelial cells where VEGFR2 was found to be phosphorylated, indicating an autocrine loop. Additionally, VEGFR2 was constitutively phosphorylated in the liver, lung, adipose, and kidney in vivo, providing evidence consistent with a role for VEGF in adult tissues. These observations support the concept that VEGF acts in the adult to stabilize mature vessels.

The observations suggest that VEGF signaling is involved, not only in choroidal vessel formation, but perhaps also in the maintenance of the choriocapillaris.