Lymphangiogenomics

 

 

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Last Update: February 18, 2008

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gene and recombinant protein therapy based on VEGF-C, VEGF-D, and their receptors is a promising new approach for the treatment of serious lymphatic and ischemic diseases and lymphatic spread of cancer metastasis. We validate the therapeutic potential of these approaches in well-established animal models, such as skin lymphedema in the Chy mice, rabbit ear lymphedema model, mouse tail lymphedema model, rabbit hind limb ischemia model, and in the pig myocardium. In addition to the validation of the treatment targets with current vectors, virus vector development is an essential part of our contribution to the consortium whereby better vectors for experimental studies and human therapy will be developed.

 

 

Responsible for this project:

 

 

Dr. Seppo Ylš-Herttuala

Dept. of Biotechnology and Molecular Medicine

A.I. Virtanen Institute

University of Kuopio

P.O. Box 1627 (Neulaniementie 2)

70211 Kuopio, Finland

Phone: +358 17 162075

Fax: +358 17 163751

E-mail: seppo.ylaherttuala(at)uku.fi

Homepage: www.uku.fi/aivi/group_molecmed.html

 

 

Selected recent publications:

  1. Tuomisto TT, Rissanen TT, Vajanto I, Korkeela A, Rutanen J, Yla-Herttuala S. HIF-VEGF-VEGFR-2, TNF-alpha and IGF pathways are upregulated in critical human skeletal muscle ischemia as studied with DNA array. Atherosclerosis 174:111-120, 2004.
     

  2. Gruchala M, Bhardwaj S, Pajusola K, Roy H, Rissanen TT, Kokina I, Kholova I, Markkanen JE, Rutanen J, Heikura T, Alitalo K, Bueler H, Yla-Herttuala S. Gene transfer into rabbit arteries with adeno-associated virus and adenovirus vectors. J Gene Med 6:545-554, 2004.
     

  3. Rutanen J, Rissanen TT, Markkanen JE, Gruchala M, Silvennoinen P, Kivela A, Hedman A, Hedman M, Heikura T, Orden MR, Stacker SA, Achen MG, Hartikainen J, Yla-Herttuala S. Adenoviral catheter-mediated intramyocardial gene transfer using the mature form of vascular endothelial growth factor-D induces transmural angiogenesis in porcine heart. Circulation 109:1029-1035, 2004.
     

  4. Leppanen O, Rutanen J, Hiltunen MO, Rissanen TT, Turunen MP, Sjoblom T, Bruggen J, Backstrom G, Carlsson M, Buchdunger E, Bergqvist D, Alitalo K, Heldin CH, Ostman A, Yla-Herttuala S. Oral imatinib mesylate (STI571/gleevec) improves the efficacy of local intravascular vascular endothelial growth factor-C gene transfer in reducing neointimal growth in hypercholesterolemic rabbits. Circulation 109:1140-1146, 2004.
     

  5. Jalkanen J, Leppanen P, Pajusola K, Narvanen O, Mahonen A, Vahakangas E, Greaves DR, Bueler H, Yla-Herttuala S. Adeno-associated virus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor reduces atherosclerotic lesion formation in LDL receptor knockout mice. Mol Ther 8:903-910, 2003.
     

  6. Rutanen J, Leppanen P, Tuomisto TT, Rissanen TT, Hiltunen MO, Vajanto I, Niemi M, Hakkinen T, Karkola K, Stacker SA, Achen MG, Alitalo K, Yla-Herttuala S. Vascular endothelial growth factor-D expression in human atherosclerotic lesions. Cardiovasc Res 59:971-979, 2003.
     

  7. Iivanainen E, Nelimarkka L, Elenius V, Heikkinen SM, Junttila TT, Sihombing L, Sundvall M, Maatta JA, Laine VJ, Yla-Herttuala S, Higashiyama S, Alitalo K, Elenius K. Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. FASEB J 17:1609-1621, 2003.
     

  8. Hedman M, Yla-Herttuala S. Gene therapy for the treatment of peripheral vascular disease and coronary artery disease. Drugs Today (Barc) 36:609-617, 2000.
     

  9. Hedman M, Hartikainen J, Syvanne M, Stjernvall J, Hedman A, Kivela A, Vanninen E, Mussalo H, Kauppila E, Simula S, Narvanen O, Rantala A, Peuhkurinen K, Nieminen MS, Laakso M, Yla-Herttuala S. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 107:2677-2683, 2003.
     

  10. Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI, Kholova I, Kauppinen RA, Achen MG, Stacker SA, Alitalo K, Yla-Herttuala S. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res 92:1098-1106, 2003.
     

  11. Hiltunen MO, Ruuskanen M, Huuskonen J, Mahonen AJ, Ahonen M, Rutanen J, Kosma VM, Mahonen A, Kroger H, Yla-Herttuala S. Adenovirus-mediated VEGF-A gene transfer induces bone formation in vivo. FASEB J 17:1147-1149, 2003.
     

  12. 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. Fibroblast growth factor 4 induces vascular permeability, angiogenesis and arteriogenesis in a rabbit hindlimb ischemia model. FASEB J 17:100-102, 2003.
     

  13. Saaristo A, Veikkola T, Tammela T, Enholm B, Karkkainen MJ, Pajusola K, Bueler H, Yla-Herttuala S, Alitalo K. Lymphangiogenic gene therapy with minimal blood vascular side effects. J Exp Med 196:719-730, 2002.
     

  14. Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21:4593-4599, 2002.
     

  15. Vajanto I, Rissanen TT, Rutanen J, Hiltunen MO, Tuomisto TT, Arve K, Narvanen O, Manninen H, Rasanen H, Hippelainen M, Alhava E, Yla-Herttuala S. Evaluation of angiogenesis and side effects in ischemic rabbit hindlimbs after intramuscular injection of adenoviral vectors encoding VEGF and LacZ.
     

  16. J Gene Med 4:371-380, 2002.
     

  17. He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94:819-825, 2002.
     

  18. Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786-1790, 2001.
     

  19. Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, Kauppinen R, Jackson DG, Kubo H, Nishikawa S, Yla-Herttuala S, Alitalo K. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7:199-205, 2001.
     

Reviews:

  1. Gruchala M, Roy H, Bhardwaj S, Yla-Herttuala S. Gene therapy for cardiovascular diseases. Curr Pharm Des 10:407-423, 2004
     

  2. Yla-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nat Med 9:694-701, 2003
     

  3. Rutanen J, Puhakka H, Yla-Herttuala S. Post-intervention vessel remodeling. Gene Ther 9:1487-1491, 2002
     

  4. Yla-Herttuala S. Gene therapy for coronary heart disease. J Intern Med 250:367-368, 2001
     

  5. Rissanen TT, Vajanto I, Yla-Herttuala S. Gene therapy for therapeutic angiogenesis in critically ischaemic lower limb - on the way to the clinic. Eur J Clin Invest 31:651-666, 2001
     

  6. Enholm B, Karpanen T, Jeltsch M, Kubo H, Stenback F, Prevo R, Jackson DG, Yla-Herttuala S, Alitalo K. Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin. Circ Res 88:623-629, 2001. Erratum in: Circ Res 89:E15, 2001