Summary

The molecular mechanisms that create, separate, and regulate the lymphatic and blood vascular systems have important implications for our understanding of the development of the vascular system, events in some forms of vascular disease, and possible new avenues for therapy for several diseases. Specific and selective markers (LYVE-1, VEGF-R3, Prox-1) now exist that can distinguish LEC from BEC differentiation at several levels, particularly the genetic and molecular levels and permit the separation of these different populations for examination of their properties. Several of these new structural and functional LEC markers permit selective targeting of LECs, and examination of their unique roles in development and their contributions to several important pathologies. These studies on LEC markers have in only a few years already provided remarkably important new evidence for the roles of lymphatics in several diseases including cancer, lymphedema, wound healing, and inflammation. These results promise to provide additional information on the roles of lymphatics in many other diseases of the immune system, development, and iatrogenic complications. Most importantly, these markers not only provide prognostic signs of specific features of disease, but also provide new mechanisms for disease processes, and consequently important new targets for prophylactic and therapeutic intervention.

Glossary

Chemokines: Soluble polypeptide factors secreted by immune system cells that stimulate some activity of other cells. Chemokines are often chemoattractants and act as tertiary messengers between cells.

Lymphedema: Swelling in the extremities caused by interstitial fluid buildup in tissues due to congenital malformation of lymphatics (primary) or surgical/traumatic (secondary) loss of lymphatic drainage (e.g., when nodes are removed or blocked).

VEGFs: A family of structurally related proteins that stimulate growth of blood and lymphatic endothelial cells and several other cell types. VEGF actions are stimulated through binding to VEGF receptors VEGFRs 1, 2, and 3. Placental growth factor (PlGF) and VEGF-B bind primarily to VEGFR-1. PlGF modulates angiogenesis and may participate in inflammation. VEGF-C and VEGF-D bind primarily to VEGFR-3 and stimulate lym-phangiogenesis rather than angiogenesis.

References

1. Sleeman, J. P., Krishnan, J., Kirkin, V, and Baumann, P. (2002). Markers for the lymphatic endothelium: in search ofthe holy grail? Microsc. Res. Tech. 55(2), 61-69.

2. Oliver, G., and Detmar, M. (2002). The rediscovery of the lymphatic system: Old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev. 16(7), 773-783.

3. Petrova, T. V., Makinen, T., Makela, T. P., Saarela, J., Virtanen, I., Ferrell, R. E., Finegold, D. N., Kerjaschki, D., Yla-Herttuala, S., and Alitalo, K. (2002). Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J. 21(17), 4593-4599.

4. Banerji, S., Ni, J., Wang, S. X., Clasper, S., Su, J., Tammi, R., Jones, M., and Jackson, D. G. (1999). LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell Biol. 144, 789-801.

5. Baldwin, M. E., Stacker, S. A., and Achen, M. G. (2002). Molecular control of lymphangiogenesis. Bioessays 24(11), 1030-1040.

6. Sleeman, J. P., Krishnan, J., Kirkin, V., and Baumann, P. (2001). Markers for the lymphatic endothelium: In search of the holy grail? Microsc. Res. Tech. 55(2), 61-69.

7. Rissanen, T. T., Markkanen, J. E., Gruchala, M., Heikura, T., Puranen, A., Kettunen, M. I., Kholova, I., Kauppinen, R. A., Achen, M. G., Stacker, S. A., Alitalo, K., and Yla-Herttuala, S. (2003). VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res. 92(10), 1098-1106.

8. Baldwin, M. E., Catimel, B., Nice, E. C., Roufail, S., Hall, N. E., Stenvers, K. L., Karkkainen, M. J., Alitalo, K., Stacker, S. A., and Achen, M. G. (2001). The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man. J. Biol. Chem. 276(22), 19166-19171.

9. Johnson-Leger, C. A., Aurrand-Lions, M., Beltraminelli, N., Fasel, N., Imhof, B. A. (2002). Junctional adhesion molecule-2 (JAM-2) pro motes lymphocyte transendothelial migration. Blood 100(7), 2479-2486.

10. Kriehuber, E., Breiteneder-Geleff, S., Groeger, M., Soleiman, A., Schoppmann, S. F., Stingl, G., Kerjaschki, D., and Maurer, D. (2001). Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J. Exp Med. 194(6), 797-808.

11. Abtahian, F., Guerriero, A., Sebzda, E., Lu, M. M., Zhou, R., Mocsai, A., Myers, E. E., Huang, B., Jackson, D. G., Ferrari, V. A., Tybulewicz, V., Lowell, C. A., Lepore, J. J., Koretzky, G. A., and Kahn, M. L. (2003). Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299(5604), 247-251.

12. Jain R. K., and Padera, T. P. (2003). Development. Lymphatics make the break. Science 299(5604), 209-210.

Further Reading

Aurrand-Lions, M., Johnson-Leger, C., Wong, C., Du Pasquier, L., and Imhof, B. A. (2001). Heterogeneity of endothelial junctions is reflected by differential expression and specific subcellular localization of the three JAM family members. Blood 98(13), 3699-3707.

Breiteneder-Geleff, S., Matsui, K., Soleiman, A., Meraner, P., Poczewski, H., Kalt, R., Schaffner, G., and Kerjaschki, D. (1997). Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis. Am. J. Pathol. 151(4), 1141-1152.

Gumkowski, F., Kaminska, G., Kaminski, M., Morrissey, L. W., and Auerbach, R. (1987). Heterogeneity of mouse vascular endothelium. In vitro studies of lymphatic, large blood vessel and microvascular endothelial cells. Blood Vessels 24(1-2), 11-23.

He, Y., Karpanen, T., and Alitalo, K. (2004). Role of lymphangiogenic factors in tumor metastasis. Biochim. Biophys. Acta 1654(1), 3-12. This review addresses the current understanding of how tumor cells pene trate the lymphatics to reach lymph nodes from primary tumor sites and summarizes recent findings in tumor/lymphatic dissemination. Podgrabinska, S., Braun, P., Velasco, P., Kloos, B., Pepper, M. S., and Skobe, M. Molecular characterization of lymphatic endothelial cells. Proc. Natl. Acad. Sci. USA 99(25), 16069-16074. Sabin, F. R. (2002). Preliminary note on the differentiation of angioblasts and the method by which they produce blood-vessels, blood-plasma, and red blood-cells as seen in the living chick. J. Hematother. Stem Cell Res. 11(1), 5-7. This paper is a reprinting of some of Dr. Rena Sabin's classical findings on the development of the vascular system from The Anatomical Record 13, 199-204 (1917). Scavelli, C., Vacca, A., Di Pietro, G., Dammacco, F., and Ribatti, D. (2004). Crosstalk between angiogenesis and lymphangiogenesis in tumor progression. Leukemia 18(6), 1054-1058. This brief review considers chemical crosstalk between elements of the blood and lymphatic vessels in the context of cancer progression. Veikkola, T., Lohela, M., Ikenberg, K., Makinen, T., Korff, T., Saaristo, A., Petrova, T., Jeltsch, M., Augustin, H. G., and Alitalo, K. (2003). Intrinsic versus microenvironmental regulation of lymphatic endothelial cell phenotype and function. FASEB J. 17(14), 2006-2013. This manuscript describes diverse differences in genes activated by growth factor receptors in blood and lymphatic endothelium and how their responses are affected by other cells in the vasculature.

Capsule Biography

Dr. Alexander has been a member of the department of Molecular and Cellular Physiology in Shreveport, LA. since 1993 and the codirector of the cell biology core, and the director of research for the department of Gas-troenterology. His laboratory primarily focuses on the roles of endothelial cells in chronic inflammation, cancer, and cardiovascular disease. The NIH has supported his work since 1993.

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