Summary

Substantial evidence based on cell culture and transgenic mouse studies indicates that NRPs are novel and significant regulators of blood vessel development. During embryonic development, NRP expression occurs early, in the blood islands of the yolk sac. NRP expression is required for the normal branching and organization of large vessels and capillaries in the developing embryo. In the developing heart, NRP1 is required for normal formation of the large vessels. In the adult, NRP expression is generally reduced, but it is strongly upregulated in blood vessels in response to vascular injury. Tumor cells are among the highest expressers of NRPs, and overexpression of NRP1 enhances tumor angio-genesis and progression. The significance of direct VEGF binding to tumor cells is unknown but might involve enhancement of tumor cell migration and survival. On the other hand, whereas overexpression of full-length NRP1 in tumor cells enhances tumor angiogenesis, overexpression of sNRP1 suppresses it.

It is now well established that NRPs are crucial for vascular development and angiogenesis. In the future, goals will include determining the molecular mechanisms by which NRP regulates EC functions and elucidating the role of NRPs in normal physiology and in pathology.

Glossary

Angiogenesis: The formation of new blood vessels that sprout from preexisting blood vessels.

Axonal guidance: Also know as axonal pathfinding and neuronal guidance. The process by which neuronal axons move to their destinations in response to chemorepellants and chemoattractants, such as the semaphorins.

Vasculogenesis: The formation of blood vessels from endothelial cell precursors, for example, arteries and veins.

Further Reading

Bagnard, D., ed. (2002). Neuropilin: from nervous system to vascular and tumor biology. Vol. 515. New York and Texas: Kluwer Academic/Plenum Publishers and Landes Bioscience. This book is a comprehensive review of neuropilin structure and function. Some of the leading investigators in the neuropilin field have contributed chapters focusing on their own scientific contributions. Ferrara, N. (1999). Molecular and biological properties of vascular endothelial growth factor. J. Mol. Med. 77, 527-543. Giger, R. J., Urquhart, E. R., Gillespie, S. K., Levengood, D. V., Ginty, D. D., and Kolodkin, A. L. (1998). Neuropilin-2 is a receptor for sem-aphorin IV: Insight into the structural basis of receptor function and specificity. Neuron 21, 1079-1092. Gu, C., Rodriguez, E. R., Reimert, D. V., Shu, T., Fritzsch, B., Richards, L. J., Kolodkin, A. L., and Ginty, D. D. (2003). Neuropilin-1 Conveys Semaphorin and VEGF Signaling during Neural and Cardiovascular Development. Dev. Cell. 5, 45-57. This work elegantly dissects the individual contributions of VEGF165 and Sema3A to the development of the vascular and the neuronal systems, respectively. In this study, an Npn-1 (NRP1) construct was produced that could bind VEGF, but not Sema3A. Knock-in of Npn-1 in mice showed that VEGF165 was needed for vascular development but Sema3A was not. Sema3A was needed, however, for normal axonal guidance. Kawasaki, T., Kitsukawa, T., Bekku, Y., Matsuda, Y., Sanbo, M., Yagi, T., and Fujisawa, H. (1999). A requirement for neuropilin-1 in embryonic vessel formation. Development 126, 4895-4902. Kitsukawa, T., Shimono, A., Kawakami, A., Kondoh, H., and Fujisawa, H. (1995). Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 121, 4309-4318. Lee, P., Goishi, K., Davidson, A. J., Mannix, R., Zon, L., and Klagsbrun, M. (2002). Neuropilin-1 is required for vascular development and is a mediator of VEGF-dependent angiogenesis in zebrafish. Proc. Natl. Acad. Sci. USA 99, 10470-10475. Zebrafish is an excellent animal model for studying vascular development. The zebrafish is transparent so that the cardiovascular system can be readily visualized. The zebrafish can survive without a functional circulation for at least four days, thereby enabling analysis of the molecular basis of vascular defects that are lethal in mice. This paper demonstrates that NRP1 is needed for normal angiogenesis but not for vasculogenesis. Furthermore, the interdependence of VEGF and NRP1 for normal vascular function is described. Matsumoto, T., and Claesson-Welsh, L. (2001). VEGF receptor signal transduction. Sci STKE 2001, RE21. Accessed at: www. stke.org/cgi/content/full/0C_sigtrans;2001/112/re21 Miao, H. Q., Soker, S., Feiner, L., Alonso, J. L., Raper, J. A., and Klagsbrun, M. (1999). Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: Functional competition of col-lapsin-1 and vascular endothelial growth factor-165. J. Cell. Biol. 146, 233-242.

Neufeld, G., Cohen, T., Shraga, N., Lange, T., Kessler, O., and Herzog, Y (2002). The neuropilins: Multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc. Med. 12, 13-19.

Soker, S., Takashima, S., Miao, H. Q., Neufeld, G., and Klagsbrun, M. (1998). Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735-745.

Takashima, S., Kitakaze, M., Asakura, M., Asanuma, H., Sanada, S., Tashiro, F., Niwa, H., Miyazaki Ji, J., Hirota, S., Kitamura, Y., Kitsukawa, T., Fujisawa, H., Klagsbrun, M., and Hori, M. (2002). Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc. Natl. Acad. Sci. USA 99, 3657-3662.

Capsule Biography

Dr. Klagsbrun is a professor in the Vascular Biology Program at Children's Hospital Boston and Harvard Medical School. He is well known for his work on vascular growth factors and their receptors. His studies on vascular molecules such as basic FGF, HB-EGF, neuropilin, and semaphorin have greatly furthered our understanding of how the vascular system is regulated and how tumor growth may be inhibited. His work is supported by grants from the National Cancer Institute.

Dr. Mamluk completed her post doctorate in the laboratory of Professor Klagsbrun. She focused her research on understanding the role of neuropilins, soluble NRPI and VEBFR-2 in vascular function and development. Currently she is conducting research for a biotechnology company aimed at developing new protein therapeutics to inhibit tumor angiogenesis.

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