SEARCH:   Advanced

Blood, 15 August 2004, Vol. 104, No. 4, pp. 1048-1057. Prepublished online as a Blood First Edition Paper on April 20, 2004; DOI 10.1182/blood-2003-08-2964. This Article Full Text (PDF) All Versions of this Article: 2003-08-2964v1 104/4/1048    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kunstfeld, R. Articles by Detmar, M. Search for Related Content PubMed PubMed Citation Articles by Kunstfeld, R. Articles by Detmar, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 5, 2003 Accepted April 7, 2004 Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia Rainer Kunstfeld, Satoshi Hirakawa, Young-Kwon Hong, Vivien Schacht, Bernhard Lange-Asschenfeldt, Paula Velasco, Charles Lin, Edda Fiebiger, Xunbin Wei, Yan Wu, Dan Hicklin, Peter Bohlen, and Michael Detmar* Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA, USA Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Boston, MA, USA Department of Pathology, Harvard Medical School, Boston, MA, USA ImClone Systems Incorporated, New York, NY, USA * Corresponding author; email: michael.detmar{at}cbrc2.mgh.harvard.edu. Vascular endothelial growth factor-A (VEGF-A) expression is upregulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions and rheumatoid arthritis. To directly characterize the biological function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation and accumulation of dermal CD4-positive T-lymphocytes and epidermal CD8-positive lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Hirakawa, M. Detmar, D. Kerjaschki, S. Nagamatsu, K. Matsuo, A. Tanemura, N. Kamata, K. Higashikawa, H. Okazaki, K. Kameda, et al. Nodal Lymphangiogenesis and Metastasis: Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget's Disease Am. J. Pathol., November 1, 2009; 175(5): 2235 - 2248. [Abstract] [Full Text] [PDF] T. E. Walshe, V. S. Dole, A. S.R. Maharaj, I. S. Patten, D. D. Wagner, and P. A. D'Amore Inhibition of VEGF or TGF-{beta} Signaling Activates Endothelium and Increases Leukocyte Rolling Arterioscler Thromb Vasc Biol, August 1, 2009; 29(8): 1185 - 1192. [Abstract] [Full Text] [PDF] J. A. Wolfram, D. Diaconu, D. A. Hatala, J. Rastegar, D. A. Knutsen, A. Lowther, D. Askew, A. C. Gilliam, T. S. McCormick, and N. L. Ward Keratinocyte but Not Endothelial Cell-Specific Overexpression of Tie2 Leads to the Development of Psoriasis Am. J. Pathol., April 1, 2009; 174(4): 1443 - 1458. [Abstract] [Full Text] [PDF] J. W. Shin, R. Huggenberger, and M. Detmar Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis Blood, September 15, 2008; 112(6): 2318 - 2326. [Abstract] [Full Text] [PDF] H. Hvid, I. Teige, P. H. Kvist, L. Svensson, and K. Kemp TPA induction leads to a Th17-like response in transgenic K14/VEGF mice: a novel in vivo screening model of psoriasis Int. Immunol., August 1, 2008; 20(8): 1097 - 1106. [Abstract] [Full Text] [PDF] N. E. Banziger-Tobler, C. Halin, K. Kajiya, and M. Detmar Growth Hormone Promotes Lymphangiogenesis Am. J. Pathol., August 1, 2008; 173(2): 586 - 597. [Abstract] [Full Text] [PDF] C. Halin, H. Fahrngruber, J. G. Meingassner, G. Bold, A. Littlewood-Evans, A. Stuetz, and M. Detmar Inhibition of Chronic and Acute Skin Inflammation by Treatment with a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Am. J. Pathol., July 1, 2008; 173(1): 265 - 277. [Abstract] [Full Text] [PDF] C. Roesli, V. Mumprecht, D. Neri, and M. Detmar Identification of the surface-accessible, lineage-specific vascular proteome by two-dimensional peptide mapping FASEB J, June 1, 2008; 22(6): 1933 - 1944. [Abstract] [Full Text] [PDF] M. Scortegagna, C. Cataisson, R. J. Martin, D. J. Hicklin, R. D. Schreiber, S. H. Yuspa, and J. M. Arbeit HIF-1{alpha} regulates epithelial inflammation by cell autonomous NF{kappa}B activation and paracrine stromal remodeling Blood, April 1, 2008; 111(7): 3343 - 3354. [Abstract] [Full Text] [PDF] K. Kajiya, R. Huggenberger, I. Drinnenberg, B. Ma, and M. Detmar Nitric oxide mediates lymphatic vessel activation via soluble guanylate cyclase {alpha}1{beta}1-impact on inflammation FASEB J, February 1, 2008; 22(2): 530 - 537. [Abstract] [Full Text] [PDF] K. Kurozumi, J. Hardcastle, R. Thakur, M. Yang, G. Christoforidis, G. Fulci, F. H. Hochberg, R. Weissleder, W. Carson, E. A. Chiocca, et al. Effect of Tumor Microenvironment Modulation on the Efficacy of Oncolytic Virus Therapy J Natl Cancer Inst, December 5, 2007; 99(23): 1768 - 1781. [Abstract] [Full Text] [PDF] C. Halin, N. E. Tobler, B. Vigl, L. F. Brown, and M. Detmar VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes Blood, November 1, 2007; 110(9): 3158 - 3167. [Abstract] [Full Text] [PDF] Y. Huang, X. Chen, M. M. Dikov, S. V. Novitskiy, C. A. Mosse, L. Yang, and D. P. Carbone Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF Blood, July 15, 2007; 110(2): 624 - 631. [Abstract] [Full Text] [PDF] L. S. Angelo and R. Kurzrock Vascular Endothelial Growth Factor and Its Relationship to Inflammatory Mediators Clin. Cancer Res., May 15, 2007; 13(10): 2825 - 2830. [Abstract] [Full Text] [PDF] J. Goldman, J. M. Rutkowski, J. D. Shields, M. C. Pasquier, Y. Cui, H. G. Schmokel, S. Willey, D. J. Hicklin, B. Pytowski, and M. A. Swartz Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis FASEB J, April 1, 2007; 21(4): 1003 - 1012. [Abstract] [Full Text] [PDF] S. Hirakawa, L. F. Brown, S. Kodama, K. Paavonen, K. Alitalo, and M. Detmar VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites Blood, February 1, 2007; 109(3): 1010 - 1017. [Abstract] [Full Text] [PDF] C. Wissmann and M. Detmar Pathways Targeting Tumor Lymphangiogenesis Clin. Cancer Res., December 1, 2006; 12(23): 6865 - 6868. [Abstract] [Full Text] [PDF] N. E. Tobler and M. Detmar Tumor and lymph node lymphangiogenesis--impact on cancer metastasis J. Leukoc. Biol., October 1, 2006; 80(4): 691 - 696. [Abstract] [Full Text] [PDF] K. Kajiya, S. Hirakawa, and M. Detmar Vascular Endothelial Growth Factor-A Mediates Ultraviolet B-Induced Impairment of Lymphatic Vessel Function Am. J. Pathol., October 1, 2006; 169(4): 1496 - 1503. [Abstract] [Full Text] [PDF] C. Xie, P. Alcaide, B. V. Geisbrecht, D. Schneider, M. Herrmann, K. T. Preissner, F. W. Luscinskas, and T. Chavakis Suppression of experimental autoimmune encephalomyelitis by extracellular adherence protein of Staphylococcus aureus J. Exp. Med., April 17, 2006; 203(4): 985 - 994. [Abstract] [Full Text] [PDF] C. A. Glass, S. J. Harper, and D. O. Bates The anti-angiogenic VEGF isoform VEGF165b transiently increases hydraulic conductivity, probably through VEGF receptor 1 in vivo J. Physiol., April 1, 2006; 572(1): 243 - 257. [Abstract] [Full Text] [PDF] M. Honma, S. A. Benitah, and F. M. Watt Role of LIM Kinases in Normal and Psoriatic Human Epidermis Mol. Biol. Cell, April 1, 2006; 17(4): 1888 - 1896. [Abstract] [Full Text] [PDF] J. Cao, N. Papadopoulou, D. Kempuraj, W. S. Boucher, K. Sugimoto, C. L. Cetrulo, and T. C. Theoharides Human Mast Cells Express Corticotropin-Releasing Hormone (CRH) Receptors and CRH Leads to Selective Secretion of Vascular Endothelial Growth Factor J. Immunol., June 15, 2005; 174(12): 7665 - 7675. [Abstract] [Full Text] [PDF] S. Hirakawa, S. Kodama, R. Kunstfeld, K. Kajiya, L. F. Brown, and M. Detmar VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis J. Exp. Med., April 4, 2005; 201(7): 1089 - 1099. [Abstract] [Full Text] [PDF] S. Hirakawa, S. Fujii, K. Kajiya, K. Yano, and M. Detmar Vascular endothelial growth factor promotes sensitivity to ultraviolet B-induced cutaneous photodamage Blood, March 15, 2005; 105(6): 2392 - 2399. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020