Angiogenesis and lymphangiogenesis, the growth of new vessels from preexisting ones, have received increasing interest due to their role in tumor growth and metastatic spread. However, vascular remodeling, associated with vascular hyperpermeability, is also a key feature of many chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, and rheumatoid arthritis. The major drivers of angiogenesis and lymphangiogenesis are vascular endothelial growth factor- (VEGF-)A and VEGF-C, activating specific VEGF receptors on the lymphatic and blood vascular endothelium. Recent experimental studies found potent anti-inflammatory responses after targeted inhibition of activated blood vessels in models of chronic inflammatory diseases. Importantly, our recent results indicate that specific activation of lymphatic vessels reduces both acute and chronic skin inflammation. Thus, antiangiogenic and prolymphangiogenic therapies might represent a new approach to treat chronic inflammatory disorders, including those due to chronic allergic inflammation. 1. Introduction According to the World Allergy Organization, allergic disorders affect 30–40% of the world’s population, and the prevalence is escalating to epidemic proportions. Much of the pathology of chronic allergic disorders such as atopic dermatitis and asthma is the long-term result of chronic allergic inflammation at the site of allergen exposure [1]. Thus, to explore additional possibilities to treat chronic allergic disorders, it is of importance to understand the distinct pathomechanisms and properties of chronic inflammation. Inflammation in general is the response of tissues to harmful stimuli such as infectious agents, antigens, or physical and chemical damage. Besides the increased inflammatory cell infiltration into the inflamed tissue, it has become clear in the recent years that acute and chronic inflammatory processes are associated with pronounced vascular remodeling. Angiogenesis and lymphangiogenesis, the growth of new blood vessels and of lymphatic vessels from preexisting ones, are involved in a number of physiological and pathological conditions such as wound healing, tumor growth, and metastatic spread [2–5]. Angiogenesis and lymphangiogenesis also occur in several chronic inflammatory conditions, including rheumatoid arthritis, inflammatory bowel disease, asthma, chronic airway inflammation, atopic dermatitis, and psoriasis [6–9]. Even though blood and lymphatic vessels are key players in acute and chronic inflammatory processes, and thus might serve as new therapeutic targets
References
[1]
S. J. Galli, M. Tsai, and A. M. Piliponsky, “The development of allergic inflammation,” Nature, vol. 454, no. 7203, pp. 445–454, 2008.
[2]
P. Carmeliet, “Angiogenesis in health and disease,” Nature Medicine, vol. 9, no. 6, pp. 653–660, 2003.
[3]
T. Karpanen and K. Alitalo, “Molecular biology and pathology of lymphangiogenesis,” Annual Review of Pathology, vol. 3, pp. 367–397, 2008.
[4]
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,” Journal of Experimental Medicine, vol. 201, no. 7, pp. 1089–1099, 2005.
[5]
V. Mumprecht and M. Detmar, “Lymphangiogenesis and cancer metastasis,” Journal of Cellular and Molecular Medicine, vol. 13, no. 8, pp. 1405–1416, 2009.
[6]
M. Detmar, L. F. Brown, K. P. Claffey et al., “Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis,” Journal of Experimental Medicine, vol. 180, no. 3, pp. 1141–1146, 1994.
[7]
S. Danese, M. Sans, C. de la Motte et al., “Angiogenesis as a novel component of inflammatory bowel disease pathogenesis,” Gastroenterology, vol. 130, no. 7, pp. 2060–2073, 2006.
[8]
P. Baluk, T. Tammela, E. Ator et al., “Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation,” Journal of Clinical Investigation, vol. 115, no. 2, pp. 247–257, 2005.
[9]
N. Thairu, S. Kiriakidis, P. Dawson, et al., “Angiogenesis as a therapeutic target in arthritis in 2011: learning the lessons of the colorectal cancer experience,” Angiogenesis, vol. 14, no. 3, pp. 223–234, 2011.
[10]
M. J. Karkkainen and T. V. Petrova, “Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis,” Oncogene, vol. 19, no. 49, pp. 5598–5605, 2000.
[11]
C. Norrmén, T. Tammela, T. V. Petrova, and K. Alitalo, “Biological basis of therapeutic lymphangiogenesis,” Circulation, vol. 123, no. 12, pp. 1335–1351, 2011.
[12]
I. M. Braverman, “Ultrastructure and organization of the cutaneous microvasculature in normal and pathologic states,” Journal of Investigative Dermatology, vol. 93, supplement 2, pp. 2S–9S, 1989.
[13]
M. Detmar and S. Hirakawa, “Vascular Biology,” in Dermatology, pp. 1679–1689, 3rd edition, 2012.
[14]
R. Huggenberger and M. Detmar, “The cutaneous vascular system in chronic skin inflammation,” Journal of Investigative Dermatology, vol. 15, no. 1, pp. 24–32, 2011.
[15]
M. Skobe and M. Detmar, “Structure, function, and molecular control of the skin lymphatic system,” Journal of Investigative Dermatology Symposium Proceedings, vol. 5, no. 1, pp. 14–19, 2000.
[16]
A. Zanini, A. Chetta, A. S. Imperatori, A. Spanevello, and D. Olivieri, “The role of the bronchial microvasculature in the airway remodelling in asthma and COPD,” Respiratory Research, vol. 11, article 132, 2010.
[17]
E. J. Gordon, N. W. Gale, and N. L. Harvey, “Expression of the hyaluronan receptor LYVE-1 is not restricted to the lymphatic vasculature; LYVE-1 is also expressed on embryonic blood vessels,” Developmental Dynamics, vol. 237, no. 7, pp. 1901–1909, 2008.
[18]
M. Kambouchner and J. F. Bernaudin, “Intralobular pulmonary lymphatic distribution in normal human lung using D2-40 antipodoplanin immunostaining,” Journal of Histochemistry and Cytochemistry, vol. 57, no. 7, pp. 643–648, 2009.
[19]
F. Sozio, A. Rossi, E. Weber, et al., “Morphometric analysis of intralobular, interlobular and pleural lymphatics in normal human lung,” Journal of Anatomy, vol. 220, no. 4, pp. 396–404, 2012.
[20]
J. S. Pober and W. C. Sessa, “Evolving functions of endothelial cells in inflammation,” Nature Reviews Immunology, vol. 7, no. 10, pp. 803–815, 2007.
[21]
J. R. Jackson, M. P. Seed, C. H. Kircher, D. A. Willoughby, and J. D. Winkler, “The codependence of angiogenesis and chronic inflammation,” The FASEB Journal, vol. 11, no. 6, pp. 457–465, 1997.
[22]
D. Ribatti, I. Puxeddu, E. Crivellato, B. Nico, A. Vacca, and F. Levi-Schaffer, “Angiogenesis in asthma,” Clinical and Experimental Allergy, vol. 39, no. 12, pp. 1815–1821, 2009.
[23]
Y. Zhang, H. Matsuo, and E. Morita, “Increased production of vascular endothelial growth factor in the lesions of atopic dermatitis,” Archives of Dermatological Research, vol. 297, no. 9, pp. 425–429, 2006.
[24]
L. Ohl, M. Mohaupt, N. Czeloth et al., “CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions,” Immunity, vol. 21, no. 2, pp. 279–288, 2004.
[25]
R. Kunstfeld, S. Hirakawa, Y. K. Hong et al., “Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia,” Blood, vol. 104, no. 4, pp. 1048–1057, 2004.
[26]
K. Kajiya and M. Detmar, “An important role of lymphatic vessels in the control of UVB-induced edema formation and inflammation,” Journal of Investigative Dermatology, vol. 126, no. 4, pp. 920–922, 2006.
[27]
Q. Zhang, Y. Lu, S. T. Proulx et al., “Increased lymphangiogenesis in joints of mice with inflammatory arthritis,” Arthritis Research and Therapy, vol. 9, no. 6, article R118, 2007.
[28]
N. Ferrara, H. P. Gerber, and J. LeCouter, “The biology of VEGF and its receptors,” Nature Medicine, vol. 9, no. 6, pp. 669–676, 2003.
[29]
A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. van Oosterom, and E. A. de Bruijn, “Vascular endothelial growth factor and angiogenesis,” Pharmacological Reviews, vol. 56, no. 4, pp. 549–580, 2004.
[30]
R. H. Adams and K. Alitalo, “Molecular regulation of angiogenesis and lymphangiogenesis,” Nature Reviews Molecular Cell Biology, vol. 8, no. 6, pp. 464–478, 2007.
[31]
G. H. Fong, J. Rossant, M. Gertsenstein, and M. L. Breitman, “Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium,” Nature, vol. 376, no. 6535, pp. 66–70, 1995.
[32]
S. Hiratsuka, O. Minowa, J. Kuno, T. Noda, and M. Shibuya, “Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 16, pp. 9349–9354, 1998.
[33]
V. Joukov, T. Sorsa, V. Kumar et al., “Proteolytic processing regulates receptor specificity and activity of VEGF-C,” The EMBO Journal, vol. 16, no. 13, pp. 3898–3911, 1997.
[34]
T. M？kinen, T. Veikkola, S. Mustjoki et al., “Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3,” The EMBO Journal, vol. 20, no. 17, pp. 4762–4773, 2001.
[35]
E. Kriehuber, S. Breiteneder-Geleff, M. Groeger et al., “Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages,” Journal of Experimental Medicine, vol. 194, no. 6, pp. 797–808, 2001.
[36]
R. Huggenberger, S. S. Siddiqui, D. Brander et al., “An important role of lymphatic vessel activation in limiting acute inflammation,” Blood, vol. 117, no. 17, pp. 4667–4678, 2011.
[37]
R. Huggenberger, S. Ullmann, S. T. Proulx, B. Pytowski, K. Alitalo, and M. Detmar, “Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation,” Journal of Experimental Medicine, vol. 207, no. 10, pp. 2255–2269, 2010.
[38]
A. Ristim？ki, K. Narko, B. Enholm, V. Joukov, and K. Alitalo, “Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C,” Journal of Biological Chemistry, vol. 273, no. 14, pp. 8413–8418, 1998.
[39]
P. Baluk, L. C. Yao, J. Feng et al., “TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice,” Journal of Clinical Investigation, vol. 119, no. 10, pp. 2954–2964, 2009.
[40]
C. Cursiefen, L. Chen, L. P. Borges et al., “VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment,” Journal of Clinical Investigation, vol. 113, no. 7, pp. 1040–1050, 2004.
[41]
L. S. Chan, “Atopic dermatitis in 2008,” Current Directions in Autoimmunity, vol. 10, pp. 76–118, 2008.
[42]
K. Yano, H. Oura, and M. Detmar, “Targeted overexpression of the angiogenesis inhibitor thrombospondin-1 in the epidermis of transgenic mice prevents ultraviolet-B-induced angiogenesis and cutaneous photo-damage,” Journal of Investigative Dermatology, vol. 118, no. 5, pp. 800–805, 2002.
[43]
L. F. Brown, T. J. Harrist, K. T. Yeo et al., “Increased expression of vascular permeability factor (vascular endothelial growth factor) in bullous pemphigoid, dermatitis herpetiformis, and erythema multiforme,” Journal of Investigative Dermatology, vol. 104, no. 5, pp. 744–749, 1995.
[44]
M. Detmar, “The role of VEGF and thrombospondins in skin angiogenesis,” Journal of Dermatological Science, vol. 24, supplement 1, pp. S78–S84, 2000.
[45]
M. Bhushan, B. McLaughlin, J. B. Weiss, and C. E. M. Griffiths, “Levels of endothelial cell stimulating angiogenesis factor and vascular endothelial growth factor are elevated in psoriasis,” British Journal of Dermatology, vol. 141, no. 6, pp. 1054–1060, 1999.
[46]
R. Zenz, R. Eferl, L. Kenner et al., “Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins,” Nature, vol. 437, no. 7057, pp. 369–375, 2005.
[47]
S. P. Raychaudhuri, M. Sanyal, S. K. Raychaudhuri, S. Dutt, and E. M. Farber, “Severe combined immunodeficiency mouse-human skin chimeras: a unique animal model for the study of psoriasis and cutaneous inflammation,” British Journal of Dermatology, vol. 144, no. 5, pp. 931–939, 2001.
[48]
Y. P. Xia, B. Li, D. Hylton, M. Detmar, G. D. Yancopoulos, and J. S. Rudge, “Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis,” Blood, vol. 102, no. 1, pp. 161–168, 2003.
[49]
C. Halin, H. Fahrngruber, J. G. Meingassner et al., “Inhibition of chronic and acute skin inflammation by treatment with a vascular endothelial growth factor receptor tyrosine kinase inhibitor,” American Journal of Pathology, vol. 173, no. 1, pp. 265–277, 2008.
[50]
M. P. Sch？n, “Animal models of psoriasis: a critical appraisal,” Experimental Dermatology, vol. 17, no. 8, pp. 703–712, 2008.
[51]
L. van der Fits, S. Mourits, J. S. A. Voerman et al., “Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis,” Journal of Immunology, vol. 182, no. 9, pp. 5836–5845, 2009.
[52]
C. E. Brewster, P. H. Howarth, R. Djukanovic, J. Wilson, S. T. Holgate, and W. R. Roche, “Myofibroblasts and subepithelial fibrosis in bronchial asthma,” American Journal of Respiratory Cell and Molecular Biology, vol. 3, no. 5, pp. 507–511, 1990.
[53]
W. R. Roche, R. Beasley, J. H. Williams, and S. T. Holgate, “Subepithelial fibrosis in the bronchi of asthmatics,” The Lancet, vol. 1, no. 8637, pp. 520–524, 1989.
[54]
B. E. Orsida, X. Li, B. Hickey, F. Thien, J. W. Wilson, and E. H. Walters, “Vascularity in asthmatic airways: relation to inhaled steroid dose,” Thorax, vol. 54, no. 4, pp. 289–295, 1999.
[55]
A. Chetta, A. Zanini, O. Torre, and D. Olivieri, “Vascular remodelling and angiogenesis in asthma: Morphological aspects and pharmacological modulation,” Inflammation and Allergy, vol. 6, no. 1, pp. 41–45, 2007.
[56]
M. Hashimoto, H. Tanaka, and S. Abe, “Quantitative analysis of bronchial wall vascularity in the medium and small airways of patients with asthma and COPD,” Chest, vol. 127, no. 3, pp. 965–972, 2005.
[57]
M. S. Dunill, “The pathology of asthma, with special reference to changes in the bronchial mucosa,” Journal of Clinical Pathology, vol. 13, pp. 27–33, 1960.
[58]
K. Asai, H. Kanazawa, K. Otani, S. Shiraishi, K. Hirata, and J. Yoshikawa, “Imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from asthmatic subjects,” Journal of Allergy and Clinical Immunology, vol. 110, no. 4, pp. 571–575, 2002.
[59]
M. Hoshino, Y. Nakamura, and Q. A. Hamid, “Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma,” Journal of Allergy and Clinical Immunology, vol. 107, no. 6, pp. 1034–1038, 2001.
[60]
A. Zanini, A. Chetta, M. Saetta et al., “Chymase-positive mast cells play a role in the vascular component of airway remodeling inasthma,” Journal of Allergy and Clinical Immunology, vol. 120, no. 2, pp. 329–333, 2007.
[61]
B. L. Gruber, M. J. Marchese, and R. Kew, “Angiogenic factors stimulate mast-cell migration,” Blood, vol. 86, no. 7, pp. 2488–2493, 1995.
[62]
M. Detmar, L. F. Brown, M. P. Sch？n et al., “Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice,” Journal of Investigative Dermatology, vol. 111, no. 1, pp. 1–6, 1998.
[63]
B. Barleon, S. Sozzani, D. Zhou, H. A. Weich, A. Mantovani, and D. Marmé, “Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1,” Blood, vol. 87, no. 8, pp. 3336–3343, 1996.
[64]
C. Feistritzer, N. C. Kaneider, D. H. Sturn, B. A. Mosheimer, C. M. K？hler, and C. J. Wiedermann, “Expression and function of the vascular endothelial growth factor receptor FLT-1 in human eosinophils,” American Journal of Respiratory Cell and Molecular Biology, vol. 30, no. 5, pp. 729–735, 2004.
[65]
A. Detoraki, R. I. Staiano, F. Granata et al., “Vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects,” Journal of Allergy and Clinical Immunology, vol. 123, no. 5, pp. 1142.e5–1149.e5, 2009.
[66]
D. M. McDonald, “Angiogenesis and remodeling of airway vasculature in chronic inflammation,” American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 10, pp. S39–S45, 2001.
[67]
K. F. Chung, D. F. Rogers, P. J. Barnes, and T. W. Evans, “The role of increased airway microvascular permeability and plasma exudation in asthma,” European Respiratory Journal, vol. 3, no. 3, pp. 329–337, 1990.
[68]
S. El-Chemaly, G. Pacheco-Rodriguez, Y. Ikeda, D. Malide, and J. Moss, “Lymphatics in idiopathic pulmonary fibrosis: new insights into an old disease,” Lymphatic Research and Biology, vol. 7, no. 4, pp. 197–203, 2009.
[69]
S. J. Leibovich, P. J. Polverini, H. M. Shepard, D. M. Wiseman, V. Shively, and N. Nuseir, “Macrophage-induced angiogenesis is mediated by tumour necrosis factor-α,” Nature, vol. 329, no. 6140, pp. 630–632, 1987.
[70]
M. Frater-Schroder, W. Risau, and R. Hallmann, “Tumor necrosis factor type α, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 15, pp. 5277–5281, 1987.
[71]
L. F. Fajardo, H. H. Kwan, J. Kowalski, S. D. Prionas, and A. C. Allison, “Dual role of tumor necrosis factor-α in angiogenesis,” American Journal of Pathology, vol. 140, no. 3, pp. 539–544, 1992.
[72]
J. Jagielska, P. R. Kapopara, G. Salguero, et al., “Interleukin-1 assembles a proangiogenic signaling module consisting of caveolin-1, tumor necrosis factor receptor-associated factor 6, p38-mitogen-activated protein kinase (MAPK), and MAPK-activated protein kinase 2 in endothelial cells,” Arteriosclerosis, Thrombosis and Vascular Biology, vol. 32, no. 5, pp. 1280–1288, 2012.
[73]
D. BenEzra, I. Hemo, and G. Maftzir, “In vivo angiogenic activity of interleukins,” Archives of Ophthalmology, vol. 108, no. 4, pp. 573–576, 1990.
[74]
F. Cozzolino, M. Torcia, D. Aldinucci et al., “Interleukin 1 is an autocrine regulator of human endothelial cell growth,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 17, pp. 6487–6491, 1990.
[75]
A. E. Koch, P. J. Polverini, S. L. Kunkel et al., “Interleukin-8 as a macrophage-derived mediator of angiogenesis,” Science, vol. 258, no. 5089, pp. 1798–1801, 1992.
[76]
C. L. Addison, T. O. Daniel, M. D. Burdick et al., “The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity,” Journal of Immunology, vol. 165, no. 9, pp. 5269–5277, 2000.
[77]
A. L. Angiolillo, H. Kanegane, C. Sgadari, G. H. Reaman, and G. Tosato, “Interleukin-15 promotes angiogenesis in vivo,” Biochemical and Biophysical Research Communications, vol. 233, no. 1, pp. 231–237, 1997.
[78]
M. Numasaki, J. I. Fukushi, M. Ono et al., “Interleukin-17 promotes angiogenesis and tumor growth,” Blood, vol. 101, no. 7, pp. 2620–2627, 2003.
[79]
C. C. Park, J. C. M. Morel, M. A. Amin, M. A. Connors, L. A. Harlow, and A. E. Koch, “Evidence of IL-18 as a novel angiogenic mediator,” Journal of Immunology, vol. 167, no. 3, pp. 1644–1653, 2001.
[80]
M. A. Amin, B. J. Rabquer, P. J. Mansfield et al., “Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases,” Annals of the Rheumatic Diseases, vol. 69, no. 12, pp. 2204–2212, 2010.
[81]
C. M. Coughlin, K. E. Salhany, M. Wysocka et al., “Interleukin-12, and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis,” Journal of Clinical Investigation, vol. 101, no. 6, pp. 1441–1452, 1998.
[82]
R. Cao, J. Farnebo, M. Kurimoto, and Y. Cao, “Interleukin-18 acts as an angiogenesis and tumor suppressor,” The FASEB Journal, vol. 13, no. 15, pp. 2195–2202, 1999.
[83]
R. M. Strieter, P. J. Polverini, S. L. Kunkel et al., “The functional role of the ELR motif in CXC chemokine-mediated angiogenesis,” Journal of Biological Chemistry, vol. 270, no. 45, pp. 27348–27357, 1995.
[84]
E. C. Keeley, B. Mehrad, and R. M. Strieter, “Chemokines as mediators of neovascularization,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, pp. 1928–1936, 2008.
[85]
Y. Fan, J. Ye, F. Shen et al., “Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 1, pp. 90–98, 2008.
[86]
M. V. Volin, J. M. Woods, M. A. Amin, M. A. Connors, L. A. Harlow, and A. E. Koch, “Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis,” American Journal of Pathology, vol. 159, no. 4, pp. 1521–1530, 2001.
[87]
R. Salcedo, K. Wasserman, H. A. Young et al., “Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells. In vivo neovascularization induced by stromal-derived factor-1α,” American Journal of Pathology, vol. 154, no. 4, pp. 1125–1135, 1999.
[88]
I. Kryczek, N. Frydman, F. Gaudin et al., “The chemokine SDF-1/CXCL12 contributes to T lymphocyte recruitment in human pre-ovulatory follicles and coordinates with lymphocytes to increase granulosa cell survival and embryo quality,” American Journal of Reproductive Immunology, vol. 54, no. 5, pp. 270–283, 2005.
[89]
R. Salcedo, M. L. Ponce, H. A. Young et al., “Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression,” Blood, vol. 96, no. 1, pp. 34–40, 2000.
[90]
K. Ebnet and D. Vestweber, “Molecular mechanisms that control leukocyte extravasation: the selectins and the chemokines,” Histochemistry and Cell Biology, vol. 112, no. 1, pp. 1–23, 1999.
