Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis
Janice A Nagy, Eliza Vasile, Dian Feng, Christian Sundberg, Lawrence F Brown, Michael J Detmar, Joel A Lawitts, Laura Benjamin, Xiaolian Tan, Eleanor J Manseau, Ann M Dvorak, Harold F Dvorak, Janice A Nagy, Eliza Vasile, Dian Feng, Christian Sundberg, Lawrence F Brown, Michael J Detmar, Joel A Lawitts, Laura Benjamin, Xiaolian Tan, Eleanor J Manseau, Ann M Dvorak, Harold F Dvorak
Abstract
Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A) is a multifunctional cytokine with important roles in pathological angiogenesis. Using an adenoviral vector engineered to express murine VEGF-A(164), we previously investigated the steps and mechanisms by which this cytokine induced the formation of new blood vessels in adult immunodeficient mice and demonstrated that the newly formed blood vessels closely resembled those found in VEGF-A-expressing tumors. We now report that, in addition to inducing angiogenesis, VEGF-A(164) also induces a strong lymphangiogenic response. This finding was unanticipated because lymphangiogenesis has been thought to be mediated by other members of the VPF/VEGF family, namely, VEGF-C and VEGF-D. The new "giant" lymphatics generated by VEGF-A(164) were structurally and functionally abnormal: greatly enlarged with incompetent valves, sluggish flow, and delayed lymph clearance. They closely resembled the large lymphatics found in lymphangiomas/lymphatic malformations, perhaps implicating VEGF-A in the pathogenesis of these lesions. Whereas the angiogenic response was maintained only as long as VEGF-A was expressed, giant lymphatics, once formed, became VEGF-A independent and persisted indefinitely, long after VEGF-A expression ceased. These findings raise the possibility that similar, abnormal lymphatics develop in other pathologies in which VEGF-A is overexpressed, e.g., malignant tumors and chronic inflammation.
Figures
References
- Hanahan, D. 1997. Signaling vascular morphogenesis and maintenance. Science. 277:48–50.
- Folkman, J. 1997. Angiogenesis and angiogenesis inhibition: an overview. EXS. 79:1–8.
- Beck, L., Jr., and P.A. D'Amore. 1997. Vascular development: cellular and molecular regulation. FASEB J. 11:365–373.
- Gale, N.W., and G.D. Yancopoulos. 1999. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev. 13:1055–1066.
- Brown, L.F., M. Detmar, K. Claffey, J.A. Nagy, D. Feng, A.M. Dvorak, and H.F. Dvorak. 1997. Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. EXS. 79:233–269.
- Carmeliet, P., and D. Collen. 1999. Role of vascular endothelial growth factor and vascular endothelial growth factor receptors in vascular development. Curr. Top. Microbiol. Immunol. 237:133–158.
- Dvorak, H.F., J.A. Nagy, D. Feng, L.F. Brown, and A.M. Dvorak. 1999. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr. Top. Microbiol. Immunol. 237:97–132.
- Ferrara, N. 1999. Vascular endothelial growth factor: molecular and biological aspects. Curr. Top. Microbiol. Immunol. 237:1–30.
- Luttun, A., M. Tjwa, L. Moons, Y. Wu, A. Angelillo-Scherrer, F. Liao, J.A. Nagy, A. Hooper, J. Priller, B. De Klerck, et al. 2002. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med. 8:831–840.
- Cao, Y., P. Linden, J. Farnebo, R. Cao, A. Eriksson, V. Kumar, J.H. Qi, L. Claesson-Welsh, and K. Alitalo. 1998. Vascular endothelial growth factor C induces angiogenesis in vivo. Proc. Natl. Acad. Sci. USA. 95:14389–14394.
- Achen, M.G., M. Jeltsch, E. Kukk, T. Makinen, A. Vitali, A.F. Wilks, K. Alitalo, and S.A. Stacker. 1998. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc. Natl. Acad. Sci. USA. 95:548–553.
- Karkkainen, M.J., R.E. Ferrell, E.C. Lawrence, M.A. Kimak, K.L. Levinson, M.A. McTigue, K. Alitalo, and D.N. Finegold. 2000. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat. Genet. 25:153–159.
- Skobe, M., T. Hawighorst, D.G. Jackson, R. Prevo, L. Janes, P. Velasco, L. Riccardi, K. Alitalo, K. Claffey, and M. Detmar. 2001. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat. Med. 7:192–198.
- Enholm, B., T. Karpanen, M. Jeltsch, H. Kubo, F. Stenback, R. Prevo, D.G. Jackson, S. Yla-Herttuala, and K. Alitalo. 2001. Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin. Circ. Res. 88:623–629.
- Jussila, L., and K. Alitalo. 2002. Vascular growth factors and lymphangiogenesis. Physiol. Rev. 82:673–700.
- Oliver, G., and M. Detmar. 2002. The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev. 16:773–783.
- Oh, S.J., M.M. Jeltsch, R. Birkenhager, J.E. McCarthy, H.A. Weich, B. Christ, K. Alitalo, and J. Wilting. 1997. VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev. Biol. 188:96–109.
- Byzova, T.V., C.K. Goldman, J. Jankau, J. Chen, G. Cabrera, M.G. Achen, S.A. Stacker, K.A. Carnevale, M. Siemionow, S.R. Deitcher, and P.E. DiCorleto. 2002. Adenovirus encoding vascular endothelial growth factor-D induces tissue-specific vascular patterns in vivo. Blood. 99:4434–4442.
- Saaristo, A., T. Veikkola, B. Enholm, M. Hytonen, J. Arola, K. Pajusola, P. Turunen, M. Jeltsch, M.J. Karkkainen, D. Kerjaschki, et al. 2002. Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes. FASEB J. 16:1041–1049.
- Pettersson, A., J.A. Nagy, L.F. Brown, C. Sundberg, E. Morgan, S. Jungles, R. Carter, J.E. Krieger, E.J. Manseau, V.S. Harvey, et al. 2000. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab. Invest. 80:99–115.
- Sundberg, C., J.A. Nagy, L.F. Brown, D. Feng, I.A. Eckelhoefer, E.J. Manseau, A.M. Dvorak, and H.F. Dvorak. 2001. Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery. Am. J. Pathol. 158:1145–1160.
- Nagy, J.A., E.S. Morgan, K.T. Herzberg, E.J. Manseau, A.M. Dvorak, and H.F. Dvorak. 1995. Pathogenesis of ascites tumor growth: angiogenesis, vascular remodeling, and stroma formation in the peritoneal lining. Cancer Res. 55:376–385.
- Feng, D., J.A. Nagy, R.A. Brekken, A. Pettersson, E.J. Manseau, K. Pyne, R. Mulligan, P.E. Thorpe, H.F. Dvorak, and A.M. Dvorak. 2000. Ultrastructural localization of the vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) receptor-2 (FLK-1, KDR) in normal mouse kidney and in the hyperpermeable vessels induced by VPF/VEGF-expressing tumors and adenoviral vectors. J. Histochem. Cytochem. 48:545–556.
- Prevo, R., S. Banerji, D.J. Ferguson, S. Clasper, and D.G. Jackson. 2001. Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J. Biol. Chem. 276:19420–19430.
- Brown, L.F., B.J. Dezube, K. Tognazzi, H.F. Dvorak, and G.D. Yancopoulos. 2000. Expression of Tie1, Tie2, and angiopoietins 1, 2, and 4 in Kaposi's sarcoma and cutaneous angiosarcoma. Am. J. Pathol. 156:2179–2183.
- Hudack, S., and P.D. McMaster. 1932. I. The permeability of the wall of the lymphatic capillary. J. Exp. Med. 56:223–238.
- Pullinger, B.D., and H.W. Florey. 1935. Some observations on the structure and functions of lymphatics: their behavior in local edema. J. Exp. Pathol. 16:49–61.
- Leak, L.V. 1970. Electron microscopic observations on lymphatic capillaries and the structural components of the connective tissue-lymph interface. Microvasc. Res. 2:361–391.
- Partanen, T.A., T. Makinen, J. Arola, T. Suda, H.A. Weich, and K. Alitalo. 1999. Endothelial growth factor receptors in human fetal heart. Circulation. 100:583–586.
- Feng, D., J. Nagy, H. Dvorak, and A. Dvorak. 2002. Ultrastructural studies define soluble macromolecular, particulate, and cellular transendothelial cell pathways in venules, lymphatic vessels, and tumor-associated microvessels in man and animals. Microsc. Res. Tech. 57:289–326.
- Skobe, M., and M. Detmar. 2000. Structure, function, and molecular control of the skin lymphatic system. J. Investig. Dermatol. Symp. Proc. 5:14–19.
- Stacker, S.A., M.E. Baldwin, and M.G. Achen. 2002. The role of tumor lymphangiogenesis in metastatic spread. FASEB J. 16:922–934.
- Zeng, H., H.F. Dvorak, and D. Mukhopadhyay. 2001. Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) receptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J. Biol. Chem. 276:26969–26979.
- McKee, P. 1996. Pathology of the Skin with Clinical Correlations. Mosby International, London. 16.74.
- Lymboussaki, A., T.A. Partanen, B. Olofsson, J. Thomas-Crusells, C.D. Fletcher, R.M. de Waal, A. Kaipainen, and K. Alitalo. 1998. Expression of the vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium of the skin and in vascular tumors. Am. J. Pathol. 153:395–403.
- Huang, H.Y., C.C. Ho, P.H. Huang, and S.M. Hsu. 2001. Co-expression of VEGF-C and its receptors, VEGFR-2 and VEGFR-3, in endothelial cells of lymphangioma. Implication in autocrine or paracrine regulation of lymphangioma. Lab. Invest. 81:1729–1734.
- Dvorak, A.M., R.A. Monahan, J.E. Osage, and G.R. Dickersin. 1980. Crohn's disease: transmission electron microscopic studies. II. Immunologic inflammatory response. Alterations of mast cells, basophils, eosinophils, and the microvasculature. Hum. Pathol. 11:606–619.
- Goldman, H. 1998. Ulcerative colitis and Crohn's disease. Pathology of the Gastrointestinal Tract. S.-C. Ming and H. Goldman, editors. Williams and Wilkins, Baltimore, MD. 673–717.
- Kanazawa, S., T. Tsunoda, E. Onuma, T. Majima, M. Kagiyama, and K. Kikuchi. 2001. VEGF, basic-FGF, and TGF-beta in Crohn's disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation. Am. J. Gastroenterol. 96:822–828.
- Griga, T., S. Werner, M. Koller, A. Tromm, and B. May. 1999. Vascular endothelial growth factor (VEGF) in Crohn's disease: increased production by peripheral blood mononuclear cells and decreased VEGF165 labeling of peripheral CD14+ monocytes. Dig. Dis. Sci. 44:1196–1201.
Source: PubMed