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VEGF Receptor Signaling in the Cardiac Lymphatics

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The Cardiac Lymphatic System

Abstract

Since the discovery of angiogenic vascular endothelial growth factor (VEGF)-A in 1983 and lymphangiogenic VEGF-C in 1997, an increasing amount of knowledge has accumulated on the essential roles of VEGF ligands and receptors in physiological and pathological angiogenesis and lymphangiogenesis. We will review the properties of VEGF ligands and receptors concentrating on their lymphatic vessel effects first in noncardiac tissues and then in normal myocardium and cardiac disease. Tissue adaptation to several stimuli such as hypoxia, pathogen invasion, and inflammation often involves coordinated changes in both blood vessels and lymphatic vessels. As lymphatic vessels are involved in the initiation and resolution of inflammation and regulation of tissue edema, VEGF family members may have important roles in myocardial lymphatics and cardiac disease.

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References

  1. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985

    Article  CAS  PubMed  Google Scholar 

  2. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425

    Article  CAS  PubMed  Google Scholar 

  3. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307

    Article  CAS  PubMed  Google Scholar 

  4. Alitalo A, Detmar M (2012) Interaction of tumor cells and lymphatic vessels in cancer ­progression. Oncogene 31:4499–4508

    Article  CAS  PubMed  Google Scholar 

  5. Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2:a006502

    PubMed  Google Scholar 

  6. Berse B, Brown LF, Van de Water L, Dvorak HF, Senger DR (1992) Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3:211–220

    CAS  PubMed  Google Scholar 

  7. Ferrara N, Winer J, Burton T (1990) Aortic smooth muscle cells express and secrete vascular endothelial growth factor. Growth Factors 5:141–148

    Article  Google Scholar 

  8. Freeman MR, Schneck FX, Gagnon ML, Corless C, Soker S, Niknejad K et al (1995) Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. Cancer Res 55:4140–4145

    CAS  PubMed  Google Scholar 

  9. McCourt M, Wang JH, Sookhai S, Redmond HP (1999) Proinflammatory mediators stimulate neutrophil-directed angiogenesis. Arch Surg 134:1325–1331

    Article  CAS  PubMed  Google Scholar 

  10. Melter M, Reinders ME, Sho M, Pal S, Geehan C, Denton MD et al (2000) Ligation of CD40 induces the expression of vascular endothelial growth factor by endothelial cells and monocytes and promotes angiogenesis in vivo. Blood 96:3801–3808

    CAS  PubMed  Google Scholar 

  11. Tomizawa S, Maruyama K, Nagasawa N, Suzuki S, Kuroume T (1984) Studies of vascular permeability factor derived from T lymphocytes and inhibitory effect of plasma on its production in minimal change nephrotic syndrome. Nephron 41:157–160

    Article  Google Scholar 

  12. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M et al (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439

    Article  CAS  PubMed  Google Scholar 

  13. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS et al (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442

    Article  CAS  PubMed  Google Scholar 

  14. Giacca M, Zacchigna S (2012) VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther 19:622–629

    Article  CAS  PubMed  Google Scholar 

  15. Maglione D, Guerriero V, Viglietto GG, Delli-Bovi PP, Persico MGM (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88:9267–9271

    Article  CAS  PubMed  Google Scholar 

  16. Koch S (2012) Neuropilin signalling in angiogenesis. Biochem Soc Trans 40:20–25

    Article  CAS  PubMed  Google Scholar 

  17. Gigante B, Tarsitano M, Cimini V, De Falco S, Persico MG (2003) Placenta growth factor is not required for exercise-induced angiogenesis. Angiogenesis 7:277–284

    Article  Google Scholar 

  18. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M et al (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583

    Article  CAS  PubMed  Google Scholar 

  19. Park JE, Chen HH, Winer J, Houck KA, Ferrara N (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269:25646–25654

    CAS  PubMed  Google Scholar 

  20. Accornero F, van Berlo JH, Benard MJ, Lorenz JN, Carmeliet P, Molkentin JD (2011) Placental growth factor regulates cardiac adaptation and hypertrophy through a paracrine mechanism. Circ Res 109:272–280

    Article  CAS  PubMed  Google Scholar 

  21. Rafii S, Avecilla S, Shmelkov S, Shido K, Tejada R, Moore MAS et al (2003) Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment. Ann N Y Academy Sci 996:49–60

    Article  CAS  Google Scholar 

  22. Adini A, Kornaga T, Firoozbakht F, Benjamin LE (2002) Placental growth factor is a survival factor for tumor endothelial cells and macrophages. Cancer Res 62:2749–2752

    CAS  PubMed  Google Scholar 

  23. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marmé D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343

    CAS  PubMed  Google Scholar 

  24. Clauss M, Weich H, Breier G, Knies U, Röckl W, Waltenberger J et al (1996) The vascular endothelial growth factor receptor Flt-1 mediates biological activities: implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 271:17629–17634

    Article  CAS  PubMed  Google Scholar 

  25. Olofsson B, Pajusola K, von Euler G, Chilov D, Alitalo K, Eriksson U (1996) Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J Biol Chem 271:19310–19317

    Article  CAS  PubMed  Google Scholar 

  26. Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O et al (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581

    Article  CAS  PubMed  Google Scholar 

  27. Aase K, von Euler G, Li X, Pontén A, Thorén P, Cao R et al (2001) Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect. Circulation 104:358–364

    Article  CAS  PubMed  Google Scholar 

  28. Bellomo D, Headrick JP, Silins GU, Paterson CA, Thomas PS, Gartside M et al (2000) Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res 86:29–35

    Article  Google Scholar 

  29. Mould AW, Tonks ID, Cahill MM, Pettit AR, Thomas R, Hayward NK et al (2003) Vegfb gene knockout mice display reduced pathology and synovial angiogenesis in both antigen-­induced and collagen-induced models of arthritis. Arthritis Rheum 48:2660–2669

    Article  CAS  PubMed  Google Scholar 

  30. Bry M, Kivelä R, Holopainen T, Anisimov A, Tammela T, Soronen J et al (2010) Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation. Circulation 122:1725–1733

    Article  CAS  PubMed  Google Scholar 

  31. Kärpänen T, Bry M, Ollila HM, Seppänen-Laakso T, Liimatta E, Leskinen H et al (2008) Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy. Circ Res 103:1018–1026

    Article  PubMed  CAS  Google Scholar 

  32. Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I et al (2010) Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464:917–921

    Article  CAS  PubMed  Google Scholar 

  33. Hagberg CE, Mehlem A, Falkevall A, Muhl L, Fam BC, Ortsäter H et al (2012) Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature 490:426–430

    Article  CAS  PubMed  Google Scholar 

  34. Ambati BK, Nozaki M, Singh N, Takeda A, Jani PD, Suthar T et al (2006) Corneal avascularity is due to soluble VEGF receptor-1. Nature 443:993–997

    Article  CAS  PubMed  Google Scholar 

  35. Kendall RL, Thomas KA (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90:10705–10709

    Article  CAS  PubMed  Google Scholar 

  36. Couper LL, Bryant SR, Eldrup-Jørgensen J, Bredenberg CE, Lindner V (1997) Vascular endothelial growth factor increases the mitogenic response to fibroblast growth factor-2 in vascular smooth muscle cells in vivo via expression of fms-like tyrosine kinase-1. Circ Res 81:932–939

    Article  CAS  PubMed  Google Scholar 

  37. Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-­regulated by hypoxia. J Biol Chem 272:23659–23667

    Article  CAS  PubMed  Google Scholar 

  38. Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 95:9349–9354

    Article  CAS  PubMed  Google Scholar 

  39. Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70

    Article  CAS  PubMed  Google Scholar 

  40. Fong GH, Zhang L, Bryce DM, Peng J (1999) Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development 126:3015–3025

    CAS  PubMed  Google Scholar 

  41. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F 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

    CAS  PubMed  Google Scholar 

  42. Pipp F, Heil M, Issbrücker K, Ziegelhoeffer T, Martin S, van den Heuvel J et al (2003) VEGFR-1-selective VEGF homologue PlGF is arteriogenic: evidence for a monocyte-­mediated mechanism. Circ Res 92:378–385

    Article  CAS  PubMed  Google Scholar 

  43. Kaipainen A, Korhonen J, Pajusola K, Aprelikova O, Persico MG, Terman BI et al (1993) The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. J Exp Med 178:2077–2088

    Article  CAS  PubMed  Google Scholar 

  44. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML et al (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66

    Article  CAS  PubMed  Google Scholar 

  45. Li J, Brown LF, Hibberd MG, Grossman JD, Morgan JP, Simons M (1996) VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol 270:H1803–H1811

    CAS  PubMed  Google Scholar 

  46. Shibuya M (1994) Role of VEGF-flt receptor system in normal and tumor angiogenesis. Adv Cancer Res 67:281–316

    Article  Google Scholar 

  47. Weis S, Shintani S, Weber A, Kirchmair R, Wood M, Cravens A et al (2004) Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J Clin Invest 113:885–894

    CAS  PubMed  Google Scholar 

  48. Yano K, Liaw PC, Mullington JM, Shih S-C, Okada H, Bodyak N et al (2006) Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med 203:1447–1458

    Article  CAS  PubMed  Google Scholar 

  49. Soker S, Takashima S, Miao HQ, Neufeld G, 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

    Article  CAS  PubMed  Google Scholar 

  50. Kärpänen T, Heckman CA, Keskitalo S, Jeltsch M, Ollila H, Neufeld G et al (2006) Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J 20:1462–1472

    Article  PubMed  CAS  Google Scholar 

  51. Xu Y, Yuan L, Mak J, Pardanaud L, Caunt M, Kasman I et al (2010) Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol 188:115–130

    Article  CAS  PubMed  Google Scholar 

  52. Jurisic G, Hajjami HM, Karaman S, Ochsenbein AM, Alitalo A, Siddiqui SS et al (2012) An unexpected role of semaphorin3a-neuropilin-1 signaling in lymphatic vessel maturation and valve formation. Circ Res 111:426–436

    Article  CAS  PubMed  Google Scholar 

  53. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ et al (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497–1506

    Article  CAS  PubMed  Google Scholar 

  54. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C et al (2004) VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113:1040–1050

    CAS  PubMed  Google Scholar 

  55. Alitalo K (2011) The lymphatic vasculature in disease. Nat Med 17:1371–1380

    Article  CAS  PubMed  Google Scholar 

  56. Kim H, Kataru RP, Koh GY (2012) Regulation and implications of inflammatory lymphangiogenesis. Trends Immunol 33:350–356

    Article  CAS  PubMed  Google Scholar 

  57. Oh SJ, Jeltsch MM, Birkenhäger R, McCarthy JE, Weich HA, Christ B et al (1997) VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188:14–24

    Article  Google Scholar 

  58. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E et al (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15:290–298

    CAS  PubMed  Google Scholar 

  59. Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V et al (1996) VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development 122:3829–3837

    CAS  PubMed  Google Scholar 

  60. Enholm B, Paavonen K, Ristimäki A, Kumar V, Gunji Y, Klefstrom J et al (1997) Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14:2475–2483

    Article  CAS  PubMed  Google Scholar 

  61. Ristimäki A, Narko K, Enholm B, Joukov V, Alitalo K (1998) Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-­C. J Biol Chem 273:8413–8418

    Article  PubMed  Google Scholar 

  62. Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, Hicklin DJ et al (2005) Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest 115:247–257

    CAS  PubMed  Google Scholar 

  63. Hamrah P, Chen L, Zhang Q, Dana MR (2003) Novel expression of vascular endothelial growth Ffctor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am J Pathol 163:12–22

    Article  Google Scholar 

  64. Nykanen AI, Sandelin H, Krebs R, Keränen MAI, Tuuminen R, Kärpänen T et al (2010) Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts. Circulation 121:1413–1422

    Article  PubMed  CAS  Google Scholar 

  65. Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Caucig C et al (2002) Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 161(3):947–956

    Article  CAS  PubMed  Google Scholar 

  66. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV et al (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74–80

    Article  CAS  PubMed  Google Scholar 

  67. Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ et al (2001) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7:199–205

    Article  CAS  PubMed  Google Scholar 

  68. Szuba A, Skobe M, Karkkainen MJ, Shin WS, Beynet DP, Rockson NB et al (2002) Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB J 16:1985–1987

    CAS  PubMed  Google Scholar 

  69. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R et al (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682

    Article  CAS  PubMed  Google Scholar 

  70. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P et al (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7:192–198

    Article  CAS  PubMed  Google Scholar 

  71. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K et al (2009) Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med 15:545–552

    Article  CAS  PubMed  Google Scholar 

  72. Benedito R, Rocha SF, Woeste M, Zamykal M, Radtke F, Casanovas O et al (2012) Notch-­dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484(7392):110–114

    Article  CAS  PubMed  Google Scholar 

  73. Saaristo A, Veikkola T, Enholm B, Hytönen M, Arola J, Pajusola K 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

    Article  CAS  PubMed  Google Scholar 

  74. Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D et al (2011) VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol 13:1202–1213

    Article  CAS  PubMed  Google Scholar 

  75. Chung ES, Chauhan SK, Jin Y, Nakao S, Hafezi-Moghadam A, Van Rooijen N et al (2009) Contribution of macrophages to angiogenesis induced by vascular endothelial growth factor receptor-3-specific ligands. Am J Pathol 175:9–19

    Article  Google Scholar 

  76. Zhang Q, Lu Y, Proulx ST, Guo R, Yao Z, Schwarz EM et al (2007) Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res Ther 9:118

    Article  CAS  Google Scholar 

  77. Shi VY, Bao L, Chan LS (2012) Inflammation-driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b+ macrophage recruitment and VEGF-C up-regulation in the IL-4-transgenic mouse model. Microcirculation 19:567–579

    Article  CAS  PubMed  Google Scholar 

  78. Hajrasouliha AR, Funaki T, Sadrai Z, Hattori T, Chauhan SK, Dana R (2012) Vascular endothelial growth factor-C promotes alloimmunity by amplifying antigen presenting cell maturation and lymphangiogenesis. Invest Ophthalmol Vis Sci 53(3):1244–1250

    Article  CAS  PubMed  Google Scholar 

  79. Krebs R, Tikkanen JM, Ropponen JO, Jeltsch M, Jokinen JJ, Herttuala SY et al (2012) Critical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis. Am J Pathol 181:1607–1620

    Article  CAS  PubMed  Google Scholar 

  80. Issa A, Le TX, Shoushtari AN, Shields JD, Swartz MA (2008) Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype. Cancer Res 69:349–357

    Article  CAS  Google Scholar 

  81. Chen L, Hamrah P, Cursiefen C, Zhang Q, Pytowski B, Streilein JW et al (2004) Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Nat Med 10:813–815

    Article  CAS  PubMed  Google Scholar 

  82. Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K et al (2001) Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol 159:893–903

    Article  CAS  PubMed  Google Scholar 

  83. Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, Antsiferova M et al (2011) An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117:4667–4678

    Article  CAS  PubMed  Google Scholar 

  84. Huggenberger R, Ullmann S, Proulx ST, Pytowski B, Alitalo K, Detmar M (2010) Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med 207:2255–2269

    Article  CAS  PubMed  Google Scholar 

  85. Zhou Q, Guo R, Wood R, Boyce BF, Liang Q, Wang YJ et al (2011) Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice. Arthritis Rheum 63:2318–2328

    Article  CAS  PubMed  Google Scholar 

  86. Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL et al (2001) The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man. J Biol Chem 276:19166–19171

    Article  CAS  PubMed  Google Scholar 

  87. Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D et al (2005) Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol 25:2441–2449

    Article  CAS  PubMed  Google Scholar 

  88. Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI et al (2003) VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res 92:1098–1106

    Article  CAS  PubMed  Google Scholar 

  89. Byzova TV, Goldman CK, Jankau J, Chen J, Cabrera G, Achen MG et al (2002) Adenovirus encoding vascular endothelial growth factor-D induces tissue-specific vascular patterns in vivo. Blood 99:4434–4442

    Article  CAS  PubMed  Google Scholar 

  90. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R et al (2001) VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7:186–191

    Article  CAS  PubMed  Google Scholar 

  91. Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K et al (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946–949

    Article  CAS  PubMed  Google Scholar 

  92. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M (2000) Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 67:7–17

    Article  Google Scholar 

  93. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA et al (2000) Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet 25:153–159

    Article  CAS  PubMed  Google Scholar 

  94. Partanen TA, Vuola P, Jauhiainen S, Lohi J, Salminen P, Pitkäranta A et al (2013) Neuropilin-2 and vascular endothelial growth factor receptor-3 are up-regulated in human vascular malformations. Angiogenesis 16(1):137–46

    Article  CAS  PubMed  Google Scholar 

  95. Martínez-Corral I, Olmeda D, Diéguez-Hurtado R, Tammela T, Alitalo K, Ortega S (2012) In vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis. Proc Natl Acad Sci USA 109:6223–6228

    Article  PubMed  Google Scholar 

  96. Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono K, Nisato RE et al (2010) Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood 115:418–429

    Article  CAS  PubMed  Google Scholar 

  97. Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M et al (2005) Inflammation-­induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 115:2363–2372

    Article  CAS  PubMed  Google Scholar 

  98. Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778

    Article  CAS  PubMed  Google Scholar 

  99. Albrecht I, Christofori G (2011) Molecular mechanisms of lymphangiogenesis in ­development and cancer. Int J Dev Biol 55:483–494

    Article  CAS  PubMed  Google Scholar 

  100. Mäkinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K et al (2005) PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 19:397–410

    Article  PubMed  CAS  Google Scholar 

  101. Niessen K, Zhang G, Ridgway JB, Chen H, Kolumam G, Siebel CW et al (2011) The Notch1-­Dll4 signaling pathway regulates mouse postnatal lymphatic development. Blood 118:1989–1997

    Article  CAS  PubMed  Google Scholar 

  102. Zheng W, Tammela T, Yamamoto M, Anisimov A, Holopainen T, Kaijalainen S et al (2011) Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor. Blood 118:1154–1162

    Article  CAS  PubMed  Google Scholar 

  103. Partanen TA, Mäkinen T, Arola J, Suda T, Weich HA, Alitalo K (1999) Endothelial growth factor receptors in human fetal heart. Circulation 100:583–586

    Article  CAS  PubMed  Google Scholar 

  104. Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K et al (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946–949

    Article  CAS  PubMed  Google Scholar 

  105. Geissler HJ, Bloch W, Förster SF, Mehlhorn U, Krahwinkel A, Kroener A et al (2003) Morphology and density of initial lymphatics in human myocardium determined by immunohistochemistry. Thorac Cardiovasc Surg 51:244–248

    Article  CAS  PubMed  Google Scholar 

  106. Geissler HJ, Dashkevich A, Fischer UM, Fries JWU, Kuhn-Régnier F, Addicks K et al (2006) First year changes of myocardial lymphatic endothelial markers in heart transplant recipients. Eur J Cardiothorac Surg 29:767–771

    Article  PubMed  Google Scholar 

  107. Lakkis FG, Arakelov A, Konieczny BT, Inoue Y (2000) Immunologic “ignorance” of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med 6:686–688

    Article  CAS  PubMed  Google Scholar 

  108. Larsen CP, Morris PJ, Austyn JM (1990) Migration of dendritic leukocytes from cardiac allografts into host spleens. A novel pathway for initiation of rejection. J Exp Med 171:307–314

    Article  CAS  PubMed  Google Scholar 

  109. Lodge-Patch I (1951) The ageing of cardiac infarcts, and its influence on cardiac rupture. Br Heart J 13:37–42

    Article  CAS  PubMed  Google Scholar 

  110. Ishikawa Y, Akasaka Y, Ishii T, Itoh K, Masuda T, Zhang L et al (2000) Sequential changes in localization of repair-related proteins (heat shock protein 70, ubiquitin and vascular endothelial growth factor) in the different stages of myocardial infarction. Histopathology 37:546–554

    Article  CAS  PubMed  Google Scholar 

  111. Ishikawa Y, Komiyama K, Masuda S, Murakami M, Akasaka Y, Ito K et al (2005) Expression of type V secretory phospholipase A in myocardial remodelling after infarction. Histopathology 47:257–267

    Article  CAS  PubMed  Google Scholar 

  112. Banai S, Jaklitsch MT, Shou M, Lazarous DF, Scheinowitz M, Biro S, Epstein SE et al (1994) Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 89:2183–2189

    Article  CAS  PubMed  Google Scholar 

  113. Ishikawa Y, Akishima-Fukasawa Y, Ito K, Akasaka Y, Tanaka M, Shimokawa R et al (2007) Lymphangiogenesis in myocardial remodelling after infarction. Histopathology 51:345–353

    Article  CAS  PubMed  Google Scholar 

  114. Libby P, Ridker PM, Hansson GK, Leducq Transatlantic Network on Atherothrombosis (2009) Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 54:2129–2138

    Article  CAS  PubMed  Google Scholar 

  115. Kholová I, Dragneva G, Cermáková P, Laidinen S, Kaskenpää N, Hazes T et al (2011) Lymphatic vasculature is increased in heart valves, ischaemic and inflamed hearts and in cholesterol-rich and calcified atherosclerotic lesions. Eur J Clin Invest 41:487–497

    Article  PubMed  Google Scholar 

  116. Gräbner R, Lötzer K, Döpping S, Hildner M, Radke D, Beer M et al (2009) Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 206:233–248

    Article  PubMed  CAS  Google Scholar 

  117. Nakano T, Nakashima Y, Yonemitsu Y, Sumiyoshi S, Chen Y-X, Akishima Y et al (2005) Angiogenesis and lymphangiogenesis and expression of lymphangiogenic factors in the atherosclerotic intima of human coronary arteries. Hum Pathol 36:330–340

    Article  CAS  PubMed  Google Scholar 

  118. Mohler ER, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS (2001) Bone formation and inflammation in cardiac valves. Circulation 103:1522–1528

    Article  PubMed  Google Scholar 

  119. Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O'Brien KD (1994) Characterization of the early lesion of “degenerative” valvular aortic stenosis: histological and immunohistochemical studies. Circulation 90:844–853

    Article  CAS  PubMed  Google Scholar 

  120. Soini Y, Salo T, Satta J (2003) Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis. Hum Pathol 34:756–763

    Article  CAS  PubMed  Google Scholar 

  121. Syväranta S, Helske S, Laine M, Lappalainen J, Kupari M, Mäyränpää MI et al (2010) Vascular endothelial growth factor-secreting mast cells and myofibroblasts: a novel self-­perpetuating angiogenic pathway in aortic valve stenosis. Arterioscler Thromb Vasc Biol 30:1220–1227

    Article  PubMed  CAS  Google Scholar 

  122. Syväranta S, Helske S, Lappalainen J, Kupari M, Kovanen PT (2012) Lymphangiogenesis in aortic valve stenosis—novel regulatory roles for valvular myofibroblasts and mast cells. Atherosclerosis 221:366–374

    Article  PubMed  CAS  Google Scholar 

  123. Aharinejad S, Schäfer R, Hofbauer R, Abraham D, Blumer R, Miksovsky A et al (2001) Impact of cardiac transplantation on molecular pathology of ET-1, VEGF-C, and mitochondrial metabolism and morphology in dilated versus ischemic cardiomyopathic patients. Transplantation 72:1043–1049

    Article  CAS  PubMed  Google Scholar 

  124. Dashkevich A, Bloch W, Antonyan A, Goebel H, Fries JUW, Schlensak C et al (2010) Immunohistochemical study of remodeling of myocardial lymphatic and blood microvascular structures in terminal heart failure: differences between ischemic and dilated cardiomyopathy. Lymphology 43:110–117

    CAS  PubMed  Google Scholar 

  125. Whitehurst B, Flister MJ, Bagaitkar J, Volk L, Bivens CM, Pickett B et al (2007) Anti-­VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int J Cancer 121:2181–2191

    Article  CAS  PubMed  Google Scholar 

  126. Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K (2010) Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 156:1499–1504

    Article  Google Scholar 

  127. Kunstfeld R, Hirakawa S, Hong Y-K, Schacht V, Lange-Asschenfeldt B, Velasco P et al (2004) Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood 104:1048–1057

    Article  CAS  PubMed  Google Scholar 

  128. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C et al (2004) VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113:1040–1050

    CAS  PubMed  Google Scholar 

  129. Iwata C, Kano MR, Komuro A, Oka M, Kiyono K, Johansson E et al (2007) Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. Cancer Res 67:10181–10189

    Article  CAS  PubMed  Google Scholar 

  130. Ristimäki A, Narko K, Enholm B, Joukov V, Alitalo K (1998) Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-­C. J Biol Chem 273:8413–8418

    Article  PubMed  Google Scholar 

  131. Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DG (2006) An inflammation-­induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med 203:2763–2777

    Article  CAS  PubMed  Google Scholar 

  132. Saban MR, Mémet S, Jackson DG, Ash J, Roig AA, Israël A et al (2004) Visualization of lymphatic vessels through NF-kappaB activity. Blood 104:3228–3230

    Article  CAS  PubMed  Google Scholar 

  133. Veikkola T, Jussila L, Mäkinen T, Karpanen T, Jeltsch M, Petrova TV et al (2001) Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 20:1223–1231

    Article  CAS  PubMed  Google Scholar 

  134. Kang S, Lee S-P, Kim KE, Kim H-Z, Mémet S, Koh GY (2009) Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages. Blood 113:2605–2613

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Alexey Dashkevich

  2. Transplantation Laboratory and Department of Cardiothoracic Surgery, University of Helsinki and Helsinki University General Hospital, Helsinki, Finland

    Karl B. Lemström & Antti I. Nykänen

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  1. Alexey Dashkevich
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  2. Karl B. Lemström
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  3. Antti I. Nykänen
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Correspondence to Alexey Dashkevich .

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  1. School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, 44106, Ohio, USA

    Ganga Karunamuni

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Dashkevich, A., Lemström, K.B., Nykänen, A.I. (2013). VEGF Receptor Signaling in the Cardiac Lymphatics. In: Karunamuni, G. (eds) The Cardiac Lymphatic System. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6774-8_9

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