Concluding Remarks

One of the most important technical problems facing the study of angiogenesis and anti-angiogenesis is the difficulty of obtaining meaningful assessments of efficacy. In vivo angiogenesis assays, such as those performed in the CAM, have allowed important progress in elucidating the mechanisms of action of several angiogenic factors and inhibitors. Nevertheless, some limitations characterize this experimental model. Nonspecific inflammatory reactions may develop as a result of grafting, inducing a secondary vasoprolifera-tive response hardly distinguishable from a direct angio-genic activity of the test material; rearrangement of existing vessels following membrane contraction may mimic neovascularization; and vasodilatation/vasoconstriction may result in apparent pro/anti-angiogenic effects, respectively (all these drawbacks may be overcome by detailed histological analysis). Finally, species-specific differences and the lack of avian-specific reagents (as well as limited genomic information) may represent serious disadvantages.

However, recent progress has contributed to improving the usefulness of the CAM as a model. For instance, retro-viral, lentiviral, and adenoviral vectors have been used in the past few years to infect the CAM (as well as the whole chick embryo), leading to the expression of the viral transgene. This allows the long-lasting presence of the gene product that is expressed directly by CAM cells, which makes feasible the study of the effects of intracellular or membrane-bound proteins as well as of dominant-negative gene products. Such an approach will shed new light on the mechanisms of blood vessel formation and inhibition in physiologic and pathologic conditions.

Glossary

Angiogenesis: The formation of new blood microvessels from preexisting ones.

Chorioallantoic membrane: Extraembryonic membrane originated by the fusion of the mesodermal layer of the allantois with the adjacent meso-dermal layer of the chorion. It mediates gas exchange between the avian embryo and the outer environment.

FGF-2: A pleiotropic growth factor endowed with a potent angiogenic activity in vitro and in vivo. It interacts with signaling tyrosine kinase receptors and heparan-sulfate proteoglycans on target cells.

VEGF: Endothelial cell growth factor crucial for embryonic vasculo-genesis and angiogenesis. It acts also as a potent vasopermeability factor. It is involved in physiologic and pathologic angiogenesis.

and autoradiographic study. Dev. Biol. 38, 237-247. This fundamental study describes the morphological characteristics of the CAM vasculature.

Djonov, V. G., Galli, A. B., and Burri, P. H. (2000). Intussusceptive arborization contributes to vascular tree formation in the chick chorio-allantoic membrane. Anat. Embryol. 202, 347-353.

Elicieri, B. P., Klemke, R., Stromblad, S., and Cheresh, D. A. (1998). Inte-grin avb3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis. J. Cell Biol. 140, 1255-1263. Integrin/growth factor receptor-mediated signaling is investigated during angiogenesis in the CAM.

Hagedorn, M., Javerzat, S., Gilges, D., Meyre, A., de Lafarge, B., Eichmann, A., and Bikfalvi. A. (2005). Accessing key steps of human tumor progression in vivo by using an avian model. Proc. Natl. Acad. Sci. U. S. A. 102, 1643-1648.

Knighton, D., Ausprunk, D., Tapper, D., and Folkman, J. (1977). Avascular and vascular phases of tumour growth in the chick embryo. Br. J. Cancer 35, 347-356.

Papoutsi, M., Tomarev, S. I., Eichmann, A., Prols, F., Christ, B., and Wilting, J. (2001). Endogenous origin of the lymphatics in the avian chorioallantoic membrane. Dev. Dyn. 222, 238-251.

Ribatti, D., Gualandris, A., Bastaki, M., Vacca, A., Iurlaro, M., Roncali, L., and Presta, M. (1997). New model for the study of angiogenesis and antiangiogenesis in the chick embryo chorioallantoic membrane: The gelatin sponge/chorioallantoic membrane assay. J. Vasc. Res. 34, 455-463.

Ribatti, D., Urbinati, C., Nico, B., Rusnati, M., Roncali, L., and Presta, M. (1995). Endogenous basic fibroblast growth factor is implicated in the vascularization of the chick embryo chorioallantoic membrane. Dev. Biol. 170, 39-49. This paper describes for the first time the role of an endogenous growth factor in CAM vascularization during development.

Ribatti, D., Vacca, A., Roncali, L., and Dammacco, F. (2000). The chick embryo chorioallantoic membrane as a model for in vivo research on anti-angiogenesis. Curr. Pharmacol. Biotechnol. 1, 73-82.

Scher, C., Haudenschild, C., and Klagsbrun, M. (1976). The chick chorioallantoic membrane as a model system for the study of tissue invasion by viral transformed cells. Cell 8, 373-382.

Schughart, K., and Accart, N. (2003). Use of adenovirus vectors for functional gene analysis in the chicken chorioallantoic membrane. Biotechniques 34, 178-183.

Capsule Biography

Dr. Ribatti is Full Professor in Human Anatomy at the School of Medicine of the University of Bari. Researches in his laboratory primarily focus on the study of angiogenesis during embryonic development and tumor progression.

Dr. Presta is Full Professor in General Pathology and has headed the Angiogenesis Laboratory at the School of Medicine of the University of Brescia since 1990. Researches in his laboratory primarily focus on the mechanisms of action of angiogenic growth factors and the development of angiogenesis inhibitors. His work has been supported in part by grants from the European Union, AIRC, and MIUR.

Further Reading

Ausprunk, D. H., Knighton, D. R., and Folkman, J. (1974). Differentiation of the vascular endothelium in the chick chorioallantois: A structural

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