78 P. Auguste & A. Bikfalvi

5.Role of FGFs in Developmental and Tumor Lymphangiogenesis

FGF-2 induces corneal lymphangiogenesis.42,85 This effect seems to be mediated through VEGF-C and possibly VEGF-D. Recently a direct mechanism of induction of lymphangiogenesis has been evidenced.86 In fact, FGF-2 binds to highand low-affinity receptors on lymphatic endothelial cells. Furthermore, Prox-1, a molecule responsible for the lymphangiogenic switch, induces expression of FGFR3 in lymphatic endothelial cells. Budding lymphatic vessels in the mouse embryo also expresses FGFR3. Finally, inhibition of FGFR3 by siRNA inhibits FGF-induced effects on lymphangiogenesis. These results indicate that FGFR3 is a crucial component for lymphangiogenic signaling. However, in tumor lymphangiogenesis, FGF signaling seems to be mainly dependent on the upregulation of VEGF-C (Larrieu Lahargue et al., unpublished results).

6.Role in Repair-Associated Angiogenesis and Ischemia Revascularization

FGF-2 has been implicated in repair-associated angiogenesis. As indicated above, FGF-2 null mice have a delay in wound healing.87 The delay in wound healing may be explained by inhibition of endothelial cell migration as observed in vitro with FGF-2 null endothelial cells36 or by inhibition of the activation of another angiogenic factor such as VEGF by FGF-2.43

FGFs are able to promote neoangiogenesis and the formation of the collateral circulation in cardiac or hindlimb models of ischemia. Several studies have shown that the administration of FGF-2 protein, naked DNA encoding FGF-1, adenovirus encoding FGF-2 in collagen-based matrices or FGF-2 bioreactors increases the formation of neovessels and collaterals.88−92

FGF-2 and FGF-1 were successfully used in the salvage of ischemic damage in different animal models such as dog,88,93,94 pig,95 rabbit89 and rat.96,97 In these models, FGFs increase the vascularization of the ischemia zone by increasing the number of arterioles and capillaries.

The route of FGF administration seems to be important. Intravenous administration of the FGF-2 protein is less effective than intra-arterial injection (intracoronary), which suggests a stability or delivery problem of the protein. These results explain, why, in some studies, FGF-2 is less effective in improving ischemic revascularization.95,98,99 However FGF-2 intrapericardial administration provides higher myocardial deposition and retention and lower systemic recirculation than intracoronary or intravenous administration.100 Alternatively, gene transfer techniques may be used instead of protein injection; naked FGF-2 plasmid DNA injected in myocardium or intracoronary adenoviral-containing FGF genes were successfully used in myocardial ischemia.101,102

In humans, FGF-2 is in therapeutic trials for coronary disease and for intermittent claudication. Intracoronary injection of FGF-2 protein in patients with ischemic heart disease not subjected to treatment with coronary arterial bypass grafting (CABG) or percutaneous transluminal angioplasty (PTAC) is well tolerated. Only a minor hypotensive effect appears at high doses after intracoronary injection.103,104 Moreover, a diminution of the ischemic zone and an improvement of myocardial perfusion are observed.104,105 However, in a second clinical study with more patients, a single bolus intracoronary injection of FGF-2 had no effect in myocardial perfusion.106 Thus, it is at present unclear whether FGF-2 protein alone is of any benefit, at least in long term, in patients with coronary artery disease. Nevertheless, FGF-2 may be efficient in combination with surgery. Indeed, FGF-2 administration in the ungraftable myocardial territory of a patient concomitantly with CABG improves myocardial revascularization.107,108

In peripheral arterial ischemic disease, intra-arterial administration of FGF-2 can improve peak walking but only if patients receive a single FGF-2 dose. The effect is greater among smokers. Nevertheless, during this phase II trial, vascularization of the leg was not studied.109

Other FGF prototypes are perhaps more efficient than FGF-2 in stimulating coronary or peripheral artery angiogenesis. This is supported by the absence of a role of endogenous FGF-2 in ischemic hindlimb revascularization in FGF-2 −/− mice.110 Indeed, FGF-4, another FGF prototype, can induce angiogenesis and arteriogenesis in a rabbit hindlimb ischemia model, and its effect is mediated by

80 P. Auguste & A. Bikfalvi

VEGF.111 In a human study, FGF-4 was delivered in myocardium by intracoronary infusion in an adenoviral vector. This allows a sustained production of the FGF-4 protein. A clear benefit was observed in treated patients.112 However, few patients (3%) developed brain and colon tumors several months after the administration, indicating a possible risk of malignant disease in patients when FGF-4 is administered via adenoviral vectors.113

The combination of FGF with other factors such as PDGF may be more efficient than the administration of single FGF protypes alone. In a recent study, Cao et al.114 have demonstrated that the administration of FGF-2 together with PDGF-BB induces synergistically the formation of vascular networks in rat and rabbit hindlimb ischemic models that remained functional after one year even after depletion of the growth factors. This constitutes a promising new venue for the treatment of ischemic disease.

7. Conclusion

Recent observations indicate that FGF prototypes certainly participate in normal and pathological vascular development. FGFs also promote the formation of larger and better organized blood vessels and can synergize with PDGFs to induce a fully mature and functional vascular network. A role in lymphangiogenesis has been also recently attributed to FGFs that is most likely dependent on the induction of VEGF-C. The respective FGF prototypes involved in vascular development are not yet fully known. Among these prototypes, FGF-2 most likely plays a role in wound healing and tumor angiogenesis.

The signal transduction mechanisms induced by FGFs in endothelial cells are now better known. However, the specific molecular events that occur during tubulogenesis, remodeling and branching remain to be elucidated. The mechanism of action of intracellular FGFs in angiogenesis is also unclear. A number of molecules that bind intracellular FGF have been discovered, however their functional role remains to be determined. The ultimate challenge is to unravel how FGFs control vascular development in an integrated fashion together with other angiogenesis regulators.

Acknowledgments

The work from our laboratory described here was supported by grants from the Association de la Recherche sur le Cancer, the Ligue Nationale contre le Cancer, Rétina France, the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Ministère de la Recherche. Due to space constraints, we are not able to quote all the relevant literature and would like to apologize to those authors whose work is not mentioned.

References

1.Bikfalvi A, Klein S, Pintucci G, Rifkin DB (1997) Biological roles of fibroblast growth factor-2. Endocr Rev 18: 26–45.

2.Javerzat S, Auguste P, Bikfalvi A (2002) The role of fibroblast growth factors in vascular development. Trends Mol Med 8: 483–489.

3.Ornitz DM, Itoh N (2001) Fibroblast growth factors. Genome Biol 2: Reviews 3005.

4.Kwan CP, Venkataraman G, Shriver Z, Raman R, Liu D, Qi Y, Varticovski L, Sasisekharan R (2001). Probing fibroblast growth factor dimerization and role of heparin-like glycosaminoglycans in modulating dimerization and signaling. J Biol Chem 276: 23421–23429.

5.Facchiano A, Russo K, Facchiano AM, De Marchis F, Facchiano F, Ribatti D, Aguzzi MS, Capogrossi MC (2003). Identification of a novel domain of fibroblast growth factor 2 controlling its angiogenic properties. J Biol Chem 278: 8751–8760.

6.Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, Linhardt RJ, Mohammadi, M (2000). Crystal structure of a ternary FGF- FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell 6: 743–750.

7.Zhang Z, Coomans C, David G (2001). Membrane heparan sulfate proteoglycansupported FGF2-FGFR1 signaling: evidence in support of the “cooperative end structures” model. J Biol Chem 276: 41921–41929.

8.Zhou Z, Wang J, Cao R, Morita H, Soininen R, Chan KM, Liu B, Cao Y, Tryggvason K (2004). Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice. Cancer Res 64: 4699–4702.

9.Rusnati M, Urbinati C, Tanghetti E, Dell’Era P, Lortat-Jacob H, Presta M (2002). Cell membrane GM1 ganglioside is a functional coreceptor for fibroblast growth factor 2. Proc Natl Acad Sci USA 99: 4367–4372.

10.Arbeit JM, Olson DC, Hanahan D (1996). Upregulation of fibroblast growth factors and their receptors during multi-stage epidermal carcinogenesis in K14HPV16 transgenic mice. Oncogene 13: 1847–1857.

11.Nakamura T, Mochizuki Y, Kanetake H, Kanda S (2001) Signals via FGF receptor 2 regulate migration of endothelial cells. Biochem Biophys Res Commun 289: 801–806.

82P. Auguste & A. Bikfalvi

12.Matsumoto T, Turesson I, Book M, Gerwins P, Claesson-Welsh L (2002). p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2-stimulated angiogenesis. J Cell Biol 156: 149–160.

13.Lin Q, Schwarz J, Bucana C, Olson EN (1997). Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276: 1404–1407.

14.Lin Q, Lu J, Yanagisawa H, Webb R, Lyons GE, Richardson JA, Olson EN (1998). Requirement of the MADS-box transcription factor MEF2C for vascular development. Development 125: 4565–4574.

15.Presta M, Tiberio L, Rusnati M, Dell’Era P, Ragnotti G (1991). Basic fibroblast growth factor requires a long-lasting activation of protein kinase C to induce cell proliferation in transformed fetal bovine aortic endothelial cells. Cell Regul 2: 719–726.

16.Wu LW, Mayo LD, Dunbar JD, Kessler KM, Baerwald MR, Jaffe EA, Wang D, Warren RS, Donner D B (2002). Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation. J Biol Chem 275: 5096–5103.

17.Sorokin A, Mohammadi M, Huang J, Schlessinger J (1994). Internalization of fibroblast growth factor receptor is inhibited by a point mutation at tyrosine. J Biol Chem 269: 17056–17061.

18.Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I (2001). Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci USA 98: 6074–6079.

19.Maffucci T, Piccolo E, Cumashi A, Iezzi M, Riley AM, Saiardi A, Godage HY, Rossi C, Broggini M, Iacobelli S, Potter BV, Innocenti P, Falasca M (2005). Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects. Cancer Res 65: 8339–8349.

20.Pourtier-Manzanedo A, Vercamer C, Van Belle E, Mattot V, Mouquet F, Vandenbunder B (2003). Expression of an Ets-1 dominant-negative mutant perturbs normal and tumor angiogenesis in a mouse ear model. Oncogene 22: 1795–1806.

21.Cross MJ, Claesson-Welsh L (2001). FGF and VEGF function in angiogenesis: signaling pathways ,biological responses and therapeutic inhibition. Trends Pharmacol Sci 22: 201–207.

22.Kanda S, Lerner EC, Tsuda S, Shono T, Kanetake H, Smithgall TE (2000). The nonreceptor protein-tyrosine kinase c-Fes is involved in fibroblast growth factor- 2-induced chemotaxis of murine brain capillary endothelial cells. J Biol Chem 275: 10105–10111.

23.LaVallee TM, Prudovsky IA, McMahon GA, Hu X, Maciag T (1998). Activation of the MAP kinase pathway by FGF-1 correlates with cell proliferation induction while activation of the Src pathway correlates with migration. J Cell Biol 141: 1647–1658.

24.Lu L, Holmqvist K, Cross M, Welsh M (2002). Role of the Src homology 2 Domain-containing protein Shb in murine brain endothelial cell proliferation and differentiation. Cell Growth Differ 13: 141–148.

25.Tsuda S, Ohtsuru A, Yamashita S, Kanetake H, Kanda S (2002). Role of c-Fyn in FGF-2-mediated tube-like structure formation by murine brain capillary endothelial cells. Biochem Biophys Res Commun 290: 1354–1360, 2002.

26.Zhan X, Plourde C, Hu X, Friesel R, Maciag T (1994). Association of fibroblast growth factor receptor-1 with c-Src correlates with association between c-Src and cortactin. J Biol Chem 269: 20221–20224,.

27.Horowitz A, Tkachenko E, Simons M (2002). Fibroblast growth factorspecific modulation of cellular response by syndecan-4. J Cell Biol 157: 715–725.

28.Li J, Shworak NW, Simons M (2002). Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites. J Cell Sci 115: 1951–1959.

29.Kovalenko D, Yang X, Nadeau RJ, Harkins LK, Friesel R (2003). Sef inhibits fibroblast growth factor signaling by inhibiting FGFR1 tyrosine phosphorylation and subsequent ERK activation. J Biol Chem 24: 24.

30.Yang RB, Ng CK, Wasserman SM, Komuves LG, Gerritsen ME, Topper JN (2003). A novel interleukin-17 receptor-like protein identified in human umbilical vein endothelial cells antagonizes basic fibroblast growth factor-induced signaling. J Biol Chem 278: 33232–33238.

31.Bikfalvi A, Klein S, Pintucci G, Quarto N, Mignatti P, Rifkin DB (1995). Differential modulation of cell phenotype by different molecular weight forms of basic fibroblast growth factor: possible intracellular signaling by the high molecular weight forms. J Cell Biol 129: 233–243.

32.Arese M, Chen Y, Florkiewicz RZ, Gualandris A, Shen B, Rifkin DB (1999). Nuclear activities of basic fibroblast growth factor: potentiation of low-serum growth mediated by natural or chimeric nuclear localization signals. Mol Biol Cell 10: 1429–1444.

33.Skjerpen CS, Wesche J, Olsnes S (2002). Identification of ribosome-binding protein p34 as an intracellular protein that binds acidic fibroblast growth factor.

J Biol Chem 8: 6.

34.Bossard C, Laurell H, Van den Berghe L, Meunier S, Zanibellato C, Prats H (2003). Translokin is an intracellular mediator of FGF-2 trafficking. Nat Cell Biol 5: 433–439.

35.Van den Berghe L, Laurell H, Huez I, Zanibellato C, Prats H, Bugler B (2000). FIF [fibroblast growth factor-2 (FGF-2)-interacting-factor], a nuclear putatively antiapoptotic factor, interacts specifically with FGF-2. Mol Endocrinol 14: 1709–1724.

36.Pintucci G, Moscatelli D, Saponara F, Biernacki PR, Baumann FG, Bizekis C, Galloway AC, Basilico C, Mignatti P (2002). Lack of ERK activation and cell migration in FGF-2–deficient endothelial cells. FASEB J 25: 25.

37.Landriscina M, Bagala C, Mandinova A, Soldi R, Micucci I, Bellum S, Prudovsky I, Maciag T (2001). Copper induces the assembly of a multiprotein aggregate

84 P. Auguste & A. Bikfalvi

implicated in the release of fibroblast growth factor 1 in response to stress. J Biol Chem 276: 25549–25557.

38.Florkiewicz RZ, Anchin J, Baird A (1998). The inhibition of fibroblast growth factor-2 export by cardenolides implies a novel function for the catalytic subunit of Na+,K+-ATPase. J Biol Chem 273: 544–551.

39.McDonnell K, Bowden ET, Cabal-Manzano R, Hoxter B, Riegel AT, Wellstein A (2005). Vascular leakage in chick embryos after expression of a secreted binding protein for fibroblast growth factors. Lab Invest 85: 747–755.

40.Tassi E, Al-Attar A, Aigner A, Swift MR, McDonnell K, Karavanov A, Wellstein A (2001). Enhancement of fibroblast growth factor (FGF) activity by an FGFbinding protein. J Biol Chem 276: 40247–40253.

41.Auguste P, Gursel DB, Lemiere S, Reimers D, Cuevas P, Carceller F, Di Santo JP, Bikfalvi A (2001). Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesisdependent and -independent mechanisms. Cancer Res 61: 1717–1726.

42.Kubo H, Cao R, Brakenhielm E, Makinen T, Cao Y, Alitalo K (2002). Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci USA 17: 17.

43.Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, Shapiro RL, Galloway AC, Rifkin DB, Mignatti P (1998). Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol 141: 1659–1673.

44.Carmeliet P (2000). Mechanisms of angiogenesis and arteriogenesis. Nat Med 6: 389–395.

45.Mailhos C, Modlich U, Lewis J, Harris A, Bicknell R, Ish-Horowicz D (2001). Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation 69: 135–144.

46.Rousseau B, Larrieu-Lahargue F, Bikfalvi A, Javerzat S (2003). Involvement of fibroblast growth factors in choroidal angiogenesis and retinal vascularization.

Exp Eye Res 77: 147–156.

47.Poole TJ, Finkelstein EB, Cox CM (2001). The role of FGF and VEGF in angioblast induction and migration during vascular development. Dev Dyn 220: 1–17.

48.Feraud O, Cao Y, Vittet D (2001). Embryonic stem cell-derived embryoid bodies development in collagen gels recapitulates sprouting angiogenesis. Lab Invest 81: 1669–1681.

49.Flamme I, Risau W (1992) Induction of vasculogenesis and hematopoiesis in vitro. Development 116: 435–439, 1992.

50.Miller DL, Ortega S, Bashayan O, Basch R, Basilico C (2002). Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol 20: 2260–2268.

51.Deng CX, Wynshaw-Boris A, Shen MM, Daugherty C, Ornitz DM, Leder P (1994). Murine FGFR-1 is required for early postimplantation growth and axial organization. Genes Dev 8: 3045–3057.

52.Arman E, Haffner-Krausz R, Chen Y, Heath JK, Lonai P (1998). Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. Proc Natl Acad Sci USA 95: 5082–5087.

53.Lee SH, Schloss DJ, Swain JL (2002). Maintenance of vascular integrity in the embryo requires signaling through the fibroblast growth factor receptor. J Biol Chem 275: 33679–33687.

54.Tomanek RJ, Sandra A, Zheng W, Brock T, Bjercke RJ, Holifield JS (2001). Vascular endothelial growth factor and basic fibroblast growth factor differentially modulate early postnatal coronary angiogenesis. Circ Res 88: 1135–1141.

55.Fulgham DL, Widhalm SR, Martin S, Coffin JD (1999). FGF-2 dependent angiogenesis is a latent phenotype in basic fibroblast growth factor transgenic mice. Endothelium 6: 185–195.

56.Yamada H, Yamada E, Kwak N, Ando A, Suzuki A, Esumi N, Zack DJ, Campochiaro PA (2000). Cell injury unmasks a latent proangiogenic phenotype in mice with increased expression of FGF2 in the retina. J Cell Physiol 185: 135–142.

57.Sheikh F, Sontag DP, Fandrich RR, Kardami E, Cattini PA (2001). Overexpression of FGF-2 increases cardiac myocyte viability after injury in isolated mouse hearts. Am J Physiol Heart Circ Physiol 280: H1039–H1050.

58.Fernandez B, Buehler A, Wolfram S, Kostin S, Espanion G, Franz WM, Niemann H, Doevendans PA, Schaper W, Zimmermann R (2000). Transgenic myocardial overexpression of fibroblast growth factor-1 increases coronary artery density and branching. Circ Res 87: 207–213.

59.Rousseau B, Dubayle D, Sennlaub F, Jeanny JC, Costet P, Bikfalvi A, Javerzat S (2000). Neural and angiogenic defects in eyes of transgenic mice expressing a dominant-negative FGF receptor in the pigmented cells. Exp Eye Res 71: 395–404.

60.Qiao J, Bush KT, Steer DL, Stuart RO, Sakurai H, Wachsman W, Nigam SK (2001). Multiple fibroblast growth factors support growth of the ureteric bud but have different effects on branching morphogenesis. Mech Dev 109: 123–135.

61.Peters K, Werner S, Liao X, Wert S, Whitsett J, Williams L (1994). Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. EMBO J 13: 3296–3301.

62.Jarecki J, Johnson E, Krasnow MA (1999). Oxygen regulation of airway branching in Drosophila is mediated by branchless FGF. Cell 99: 211–220.

63.Lee SH, Schloss DJ, Jarvis L, Krasnow MA, Swain JL (2000). Inhibition of angiogenesis by a mouse sprouty protein. J Biol Chem 26: 26.

64.Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, Hanahan D (1991). Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell 66: 1095–1104.

65.Nguyen M, Watanabe H, Budson AE, Richie JP, Folkman J (1993). Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients. J Natl Cancer Inst 85: 241–242.

66.Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J (1994). Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in

86 P. Auguste & A. Bikfalvi

the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 86: 356–361.

67.Huss WJ, Hanrahan CF, Barrios RJ, Simons JW, Greenberg NM (2001). Angiogenesis and prostate cancer: identification of a molecular progression switch. Cancer Res 61: 2736–2743.

68.Huss WJ, Barrios RJ, Foster BA, Greenberg NM (2003). Differential expression of specific FGF ligand and receptor isoforms during angiogenesis associated with prostate cancer progression. Prostate 54: 8–16.

69.Rofstad EK, Halsor EF (2000). Vascular endothelial growth factor, interleukin 8, platelet-derived endothelial cell growth factor, basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts. Cancer Res 60: 4932–4938.

70.Wang Y, Becker D (1997). Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nat Med 3: 887–893.

71.Stan AC, Nemati MN, Pietsch T, Walter GF, Dietz H (1995). In vivo inhibition of angiogenesis and growth of the human U-87 malignant glial tumor by treatment with an antibody against basic fibroblast growth factor. J Neurosurg 82: 1044–1052.

72.Miraux S, Lemiere S, Pineau R, Pluderi M, Canioni P, Franconi JM, Thiaudiere E, Bello L, Bikfalvi A, Auguste P (2004). Inhibition of FGF receptor activity in glioma implanted into the mouse brain using the tetracyclin-regulated expression system. Angiogenesis 7: 105–113.

73.Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999). Vessel cooption, regression, growth in tumors mediated by angiopoietins and VEGF. Science 284: 1994–1998.

74.Zagzag D, Amirnovin R, Greco MA, Yee H, Holash J, Wiegand SJ, Zabski S, Yancopoulos GD, Grumet M (2000). Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 80: 837–849.

75.Ogawa T, Takayama K, Takakura N, Kitano S, Ueno H (2002). Antitumor angiogenesis therapy using soluble receptors: enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor. Cancer Gene Ther 9: 633–640.

76.Compagni A, Wilgenbus P, Impagnatiello MA, Cotten M, Christofori G (2000). Fibroblast growth factors are required for efficient tumor angiogenesis. Cancer Res 60: 7163–7169.

77.Billottet C, Janji B, Thiery JP, Jouanneau J (2002). Rapid tumor development and potent vascularization are independent events in carcinoma producing FGF-1 or FGF-2. Oncogene 21: 8128–8139.

78.Jouanneau J, Plouet J, Moens G, Thiery JP (1997). FGF-2 and FGF-1 expressed in rat bladder carcinoma cells have similar angiogenic potential but different tumorigenic properties in vivo. Oncogene 14: 671–676.

79.Giavazzi R, Giuliani R, Coltrini D, Bani MR, Ferri C, Sennino B, Tosatti MP, Stoppacciaro A, Presta M (2001). Modulation of tumor angiogenesis by

conditional expression of fibroblast growth factor-2 affects early but not established tumors. Cancer Res 61:309–317.

80.Pepper MS, Ferrara N, Orci L, Montesano R (1992). Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 189: 824–831.

81.Giavazzi R, Sennino B, Coltrini D, Garofalo A, Dossi R, Ronca R, Tosatti MP, Presta M (2003). Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol 162: 1913–1926.

82.Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005). Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8: 299–309.

83.Czubayko F, Liaudet-Coopman ED, Aigner A, Tuveson AT, Berchem GJ, Wellstein AA (1997). A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. Nat Med 3: 1137–1140.

84.Bossard C, Van den Berghe L, Laurell H, Castano C, Cerutti M, Prats AC, Prats H (2004). Antiangiogenic properties of fibstatin, an extracellular FGF-2- binding polypeptide. Cancer Res 64: 7507–7512.

85.Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A (2004). Dosedependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 101: 11658–11663.

86.Shin JW, Min M, Larrieu-Lahargue F, Canron X, Kunstfeld R, Nguyen L, Henderson JE, Bikfalvi A, Detmar M, Hong YK (2006). Prox1 promotes lineagespecific expression of FGF receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. Mol Biol Cell 17: 576–584.

87.Ortega S, Ittmann M, Tsang SH, Ehrlich M, Basilico C (1998). Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc Natl Acad Sci USA 95: 5672–5677.

88.Yanagisawa-Miwa A, Uchida Y, Nakamura F, Tomaru T, Kido H, Kamijo T, Sugimoto T, Kaji K, Utsuyama M, Kurashima C, et al. (1992). Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science 257: 1401–1403.

89.Tabata H, Silver M, Isner JM (1997). Arterial gene transfer of acidic fibroblast growth factor for therapeutic angiogenesis in vivo: critical role of secretion signal in use of naked DNA. Cardiovasc Res 35: 470–479.

90.Horvath KA, Doukas J, Lu CY, Belkind N, Greene R, Pierce GF, Fullerton DA (2002). Myocardial functional recovery after fibroblast growth factor 2 gene therapy as assessed by echocardiography and magnetic resonance imaging. Ann Thorac Surg 74: 481–486; discussion 487.

91.Rinsch C, Quinodoz P, Pittet B, Alizadeh N, Baetens D, Montandon D, Aebischer P, Pepper MS (2001). Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia. Gene Ther 8: 523–533.

92.Yamamoto M, Sakakibara Y, Nishimura K, Komeda M, Tabata Y (2003). Improved therapeutic efficacy in cardiomyocyte transplantation for myocardial

88 P. Auguste & A. Bikfalvi

infarction with release system of basic fibroblast growth factor. Artif Organs 27: 181–184.

93.Lazarous DF, Scheinowitz M, Shou M, Hodge E, Rajanayagam S, Hunsberger S, Robison WG, Jr, Stiber JA, Correa R, Epstein SE, et al. (1995). Effects of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart. Circulation 91: 145–153.

94.Lazarous DF, Shou M, Scheinowitz M, Hodge E, Thirumurti V, Kitsiou AN, Stiber JA, Lobo AD, Hunsberger S, Guetta E, Epstein SE, Unger EF (1996). Comparative effects of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. Circulation 94: 1074–1082.

95.Sato K, Laham RJ, Pearlman JD, Novicki D, Sellke FW, Simons M, Post MJ (2000). Efficacy of intracoronary versus intravenous FGF-2 in a pig model of chronic myocardial ischemia. Ann Thorac Surg 70: 2113–2118.

96.Yang HT, Feng Y (2000). bFGF increases collateral blood flow in aged rats with femoral artery ligation. Am J Physiol Heart Circ Physiol 278: H85–H93.

97.Yang HT, Yan Z, Abraham JA, Terjung RL (2001). VEGF (121)- and bFGFinduced increase in collateral blood flow requires normal nitric oxide production.

Am J Physiol Heart Circ Physiol 280: H1097–H1104.

98.Lazarous DF, Shou M, Stiber JA, Dadhania DM, Thirumurti V, Hodge E, Unger EF (1997). Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic distribution. Cardiovasc Res 36: 78–85.

99.Rajanayagam MA, Shou M, Thirumurti V, Lazarous DF, Quyyumi AA, Goncalves L, Stiber J, Epstein SE, Unger EF (2000). Intracoronary basic fibroblast growth factor enhances myocardial collateral perfusion in dogs. J Am Coll Cardiol 35: 519–526.

100.Laham RJ, Rezaee M, Post M, Xu X, Sellke FW (2003). Intrapericardial administration of basic fibroblast growth factor: myocardial and tissue distribution and comparison with intracoronary and intravenous administration. Catheter Cardiovasc Interv 58: 375–381.

101.Gao MH, Lai NC, Hammond HK (2005). Signal Peptide Increases the Efficacy of Angiogenic Gene Transfer for Treatment of Myocardial Ischemia. Hum Gene Ther 16: 1058–1064.

102.Heilmann CA, Attmann T, Thiem A, Haffner E, Beyersdorf F, Lutter G (2003). Gene therapy in cardiac surgery: intramyocardial injection of naked plasmid DNA for chronic myocardial ischemia. Eur J Cardiothorac Surg 24: 785–793.

103.Lazarous DF, Unger EF, Epstein SE, Stine A, Arevalo JL, Chew EY, Quyyumi AA (2000). Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial. J Am Coll Cardiol 36: 1239–1244.

104.Laham RJ, Chronos NA, Pike M, Leimbach ME, Udelson JE, Pearlman JD, Pettigrew RI, Whitehouse MJ, Yoshizawa C, Simons M (2000). Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study. J Am Coll Cardiol 36: 2132–2139.

105.Udelson JE, Dilsizian V, Laham RJ, Chronos N, Vansant J, Blais M, Galt JR, Pike M, Yoshizawa C, Simons M (2000). Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease. Circulation 102: 1605–1610.

106.Simons M, Annex BH, Laham RJ, Kleiman N, Henry T, Dauerman H, Udelson JE, Gervino EV, Pike M, Whitehouse MJ, Moon T, Chronos NA (2002). Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 105: 788–793.

107.Pecher P, Schumacher BA (2000). Angiogenesis in ischemic human myocardium: clinical results after 3 years. Ann Thorac Surg 69: 1414–1419.

108.Ruel M, Laham RJ, Parker JA, Post MJ, Ware JA, Simons M, Sellke FW (2002). Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. J Thorac Cardiovasc Surg 124: 28–34.

109.Lederman RJ, Mendelsohn FO, Anderson RD, Saucedo JF, Tenaglia AN, Hermiller JB, Hillegass WB, Rocha-Singh K, Moon TE, Whitehouse MJ, Annex BH (2002). Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 359: 2053–2058.

110.Sullivan CJ, Doetschman T, Hoying JB (2002). Targeted disruption of the Fgf2 gene does not affect vascular growth in the mouse ischemic hindlimb. J Appl Physiol 93: 2009–2017.

111.Rissanen TT, Markkanen JE, Arve K, Rutanen J, Kettunen MI, Vajanto I, Jauhiainen S, Cashion L, Gruchala M, Narvanen O, Taipale P, Kauppinen RA, Rubanyi GM, Yla-Herttuala S (2003). Fibroblast growth factor 4 induces vascular permeability, angiogenesis and arteriogenesis in a rabbit hindlimb ischemia model. FASEB J 17: 100–102.

112.Grines CL, Watkins MW, Helmer G, Penny W, Brinker J, Marmur JD, West A, Rade JJ, Marrott P, Hammond HK, Engler RL (2002). Angiogenic gene therapy (AGENT) trial in patients with stable angina pectoris. Circulation 105: 1291–1297.

113.Bliznakov EG (2002). Therapeutic angiogenesis: hope or hype. Circulation 106: e220–e221; author reply e220–e221.

114.Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, Leboulch P, Cao Y (2003). Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med 31: 31.

This page intentionally left blank