Conclusion

It is clear that the VEGF isoforms differ in their biochemical properties. Analysis of several model systems has demonstrated that individual isoforms can differentially affect both developmental and pathological angiogenesis. Further work is necessary to elucidate the precise roles of each isoform. Such work may eventually make it possible to specifically target individual isoforms during pathological angiogenesis.

Glossary

CMV: Cytomegalovirus promoter, a ubiquitous, strong promoter often used in overexpression studies.

Exons: The coding sequences of genes. In mammalian cells, exons within genes are interrupted by introns, which are noncoding sequences. HSPGs: Heparin sulfate proteoglycans.

Ischemia: A condition in which tissues become oxygen deficient as a result of several pathological conditions. As a result, the tissue is relatively hypoxic, leading to upregulation of the VEGF gene.

Isoforms: Different forms of a protein, derived from a single gene that result from alternative splicing.

References

1. Jingjing, L., Srinivasan, B., and Roque, R. S. (2001). Ectodomain shedding of VEGF183, a novel isoform of vascular endothelial growth factor, promotes its mitogenic activity in vitro. Angiogenesis 4, 103-112.

2. Soker, S., Gollamudi-Payne, S., Fidder, H., Charmahelli, H., and Klagsbrun, M. (1997). Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation by a peptide corresponding to the exon 7-encoded domain of VEGF165. J. Biol. Chem. 272, 31582-31588.

3. Ng, Y. S., Rohan, R., Sunday, M. E., Demello, D. E., and D'Amore, P. A. (2001). Differential expression of VEGF isoforms in mouse during development and in the adult. Dev. Dyn. 220, 112-121. In this paper, it was demonstrated that VEGF isoform levels vary during development and in the adult mouse. Data suggest that VEGF isoforms have different roles in developing and adult tissues to form and maintain vascular patterns.

4. Carmeliet, P., Ng, Y. S., Nuyens, D., Theilmeier, G., Brusselmans, K., Cornelissen, I., Ehler, E., Kakkar, V. V., Stalmans, I., Mattot, V., Perriard, J. C., Dewerchin, M., Flameng, W., Nagy, A., Lupu, F., Moons, L., Collen, D., D'Amore, P. A., and Shima, D. T. (1999). Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF 164 and VEGF188. Nat. Med. 5, 495-502. One of the first reports that VEGF isoforms in vivo are not functionally equivalent. Mice that express only the smallest isoform (VEGF120) were generated, and were shown to die shortly after birth, compared to mice with a wild-type complement of VEGF.

5. Stalmans, I., Ng, Y. S., Rohan, R., Fruttiger, M., Bouche, A., Yuce, A., Fujisawa, H., Hermans, B., Shani, M., Jansen, S., Hicklin, D., Anderson, D. J., Gardiner, T., Hammes, H. P., Moons, L., Dewerchin, M., Collen, D., Carmeliet, P., and D'Amore, P. A. (2002). Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J. Clin. Invest. 109, 327-336.

6. Ishida, S., Usui, T., Yamashiro, K., Kaji, Y., Amano, S., Ogura, Y., Hida, T., Oguchi, Y., Ambati, J., Miller, J. W., Gragoudas, E. S., Ng, Y. S., D'Amore, P. A., Shima, D. T., and Adamis, A. P. (2003). VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J. Exp. Med. 198, 483-489.

7. Zelzer, E., Mclean, W., Ng, Y. S., Fukai, N., Reginato, A. M., Lovejoy, S., D'Amore, P. A., and Olsen, B. R. (2002). Skeletal defects in

VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 129, 1893-1904.

8. Cheng, S. Y., Nagane, M., Huang, H. S., and Cavenee, W. K. (1997). Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF121 and VEGF165 but not VEGF189. Proc. Nat. Acad. Sci. USA 94, 12081-12087.

9. Grunstein, J., Masbad, J. J., Hickey, R., Giordano, F., and Johnson, R. S. (2000). Isoforms of vascular endothelial growth factor act in coordinate fashion to recruit and expand tumor vasculature. Mol. Cell. Biol. 120, 7282-7291. A thorough analysis of the influence of different VEGF isoforms on tumor formation. It was shown that the different isoforms vary in their abilities to vascularize tumors and promote tumor growth when compared with VEGF-null or wild-type cells.

Robinson, C. J., and Stringer, S. E. (2001). The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J. Cell. Sci. 114, 853-865.

Capsule Biographies

Patricia A. D'Amore received her Ph.D. from Boston University and completed a postdoctoral fellowship at Johns Hopkins Medical School. She is currently Professor of Ophthalmology and Pathology at Harvard Medical School, a Research Associate at Children's Hospital, and a Senior Scientist at the Schepens Eye Research Institute in Boston.

Eric B. Finkelstein earned his Ph.D. in 2001 at the SUNY Upstate Medical University in Syracuse, New York, working in Dr. Thomas J. Poole's laboratory on the role of VEGF in blood vessel morphogenesis. He is currently a postdoctoral fellow in Dr. D'Amore's laboratory in Boston, studying endothelial cell differentiation and the function of VEGF isoforms.

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