Angiogenesis, controlled by both stimulatory and inhibitory factors, is essential for organ and tissue development and critical for many pathological processes, including inflammation, wound and fracture healing and tumor growth. Inactivation of the major pro-angiogenic factor VEGF in the neuroepithelial-derived retinal pigment epithelium (RPE) results in absence of choriocapillaris and loss of visual function (Marneros et al., 2005). In contrast, increased activity of VEGF induces choroidal neovascularization (CNV) with sprouting capillaries destroying retinal structure and function. Under normal conditions, RPE cells restrict the pro-angiogenic effects of VEGF by synthesizing anti-angiogenic factors. One of these, collagen XVIII, is a component of the RPE and choroidal capillary basement membranes. Cleavage of collagen XVIII releases an anti-angiogenic fragment, endostatin. Collagen XVIII/endostatin levels are reduced in eyes of patients with age-related macular degeneration (AMD), and recent studies demonstrate that physiological levels of endostatin can inhibit CNV (Marneros et al., 2007). Thus, endostatin administration may be an effective complement to anti-VEGF therapy in treatment of patients with AMD. Loss of a factor that inhibits VEGF action is also part of the mechanism underlying infantile hemangioma, the most common tumor of infancy. Hemangiomas appear and grow rapidly after birth for weeks/months and slowly regress over 7–10 years. Low expression levels of VEGFR-1 in hemangioma cells result in excessive VEGF signaling through VEGFR-2 (Jinnin et al., submitted). We have identified mutations in cell surface receptors that control the transcriptional activation of VEGFR-1 in hemangioma endothelial cells. Addition of recombinant, soluble VEGFR-1 protein or antibodies against VEGF to hemangioma cells normalizes the excessive signaling through VEGFR-2. The findings suggest a therapy for treatment of rapidly growing and clinically problematic infantile hemangiomas.

References:

Jinnin, M., Medici, D., Park, L., Liu, Y., Boye, E. & Olsen, B. R. (Submitted for publication). Marneros, A. G., Fan, J., Yokoyama, Y., Gerber, H. P., Ferrara, N., Crouch, R. K. & Olsen, B. R. 2005. Am J Pathol. 167, 1451–1459. Marneros, A. G., She, H., Zambarakji, H., Hashizume, H., Connoly, E. J., Kim, I., Gragoudas, E. S., Miller, J. W. & Olsen, B. R. 2007. FASEB J first published on May 25, 2007 as doi:10.1096/fj.07-8422com.