Hostname: page-component-cd9895bd7-7cvxr Total loading time: 0 Render date: 2024-12-26T08:57:43.407Z Has data issue: false hasContentIssue false
  • English
  • Français

Lymphangiogenesis in renal diseases: passive bystander or active participant?

Published online by Cambridge University Press:  25 September 2014

Saleh Yazdani ,
Gerjan Navis ,
Jan-Luuk Hillebrands ,
Harry van Goor  and
Jacob van den Born
Saleh Yazdani*
Affiliation:
Department of Medicine, Division of Nephrology, University Medical Centre Groningen and University of Groningen, the Netherlands
Gerjan Navis
Affiliation:
Department of Medicine, Division of Nephrology, University Medical Centre Groningen and University of Groningen, the Netherlands
Jan-Luuk Hillebrands
Affiliation:
Department of Pathology and Medical Biology, Division of Pathology, University Medical Centre Groningen and University of Groningen, the Netherlands
Harry van Goor
Affiliation:
Department of Pathology and Medical Biology, Division of Pathology, University Medical Centre Groningen and University of Groningen, the Netherlands
Jacob van den Born
Affiliation:
Department of Medicine, Division of Nephrology, University Medical Centre Groningen and University of Groningen, the Netherlands
*
*Corresponding author: Saleh Yazdani, Department of Medicine, Division of Nephrology, University Medical Center Groningen, the Netherlands. E-mail: sy.gr.nl@gmail.com; s.yazdani@umcg.nl
Get access Rights & Permissions [Opens in a new window]

Abstract

Lymphatic vessels (LVs) are involved in a number of physiological and pathophysiological processes such as fluid homoeostasis, immune surveillance, and resolution of inflammation and wound healing. Lymphangiogenesis, the outgrowth of existing LVs and the formation of new ones, has received increasing attention over the past decade on account of its prominence in organ physiology and pathology, which has been enabled by the development of specific tools to study lymph vessel functions. Several studies have been devoted to renal lymphatic vasculature and lymphangiogenesis in kidney diseases, such as chronic renal transplant dysfunction, primary renal fibrotic disorders, proteinuria, diabetic nephropathy and renal inflammation. This review describes the most recent findings on lymphangiogenesis, with a specific focus on renal lymphangiogenesis and its impact on renal diseases. We suggest renal lymphatics as a possible target for therapeutic interventions in renal medicine to dampen tubulointerstitial tissue remodelling and improve renal functioning.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 16 , 2014 , e15
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Loukas, M. et al. (2011) The Lymphatic System: A Historical Perspective, Clinical Anatomy, New York, N.Y., 24, 807-816Google Scholar
2Wiig, H. and Swartz, M. A. (2012) Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiological Reviews 92, 1005-1060Google Scholar
3Florey, H. (1927) Observations on the contractility of lacteals: Part I. The Journal of Physiology 62, 267-272Google Scholar
4Reddy, N. P. and Staub, N. C. (1981) Intrinsic propulsive activity of thoracic duct perfused in anesthetized dogs. Microvascular Research 21, 183-192CrossRefGoogle ScholarPubMed
5Trzewik, J. et al. (2001) Evidence for a second valve system in lymphatics: endothelial microvalves. FASEB Journal 15, 1711-1717Google Scholar
6Sabin, FR. (1902) On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. American Journal of Anatomy 1, 367-391Google Scholar
7Srinivasan, R. S. et al. (2007) Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes & Development 21, 2422-2432Google Scholar
8Huntington, G. S. and McClure, C. F. W. (1910) The anatomy and development of the jugular lymph sacs in the domestic cat (Felis domestica). American Journal of Anatomy 10, 177-311Google Scholar
9Wigle, J. T. and Oliver, G. (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98, 769-778Google Scholar
10van der Putte, S. C. (1975) The development of the lymphatic system in man. Advances in Anatomy, Embryology, and Cell Biology 51, 3-60Google Scholar
11Schulte-Merker, S., Sabine, A. and Petrova, T. V. (2011) Lymphatic vascular morphogenesis in development, physiology, and disease. The Journal of Cell Biology 193, 607-618Google Scholar
12Yang, Y. and Oliver, G. (2014) Development of the mammalian lymphatic vasculature. The Journal of Clinical Investigation 124, 888-97Google Scholar
13Koltowska, K. et al. (2013) Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature. Development (Cambridge, England) 140, 1857-1870Google Scholar
14Albertine, K. H. and O'Morchoe, C. C. (1980) An Integrated light and electron microscopic study on the existence of intramedullary lymphatics in the dog kidney. Lymphology 13, 100-106Google Scholar
15Cuttino, J. T. et al. (1985) Renal medullary lymphatics: microradiographic, light, and electron microscopic studies in pigs. Lymphology 18, 24-30Google Scholar
16Peirce, EC 2nd. (1944) Renal lymphatics. The Anatomical Record 90, 315-335Google Scholar
17Eliska, O. (1984) Topography of intrarenal lymphatics. Lymphology 17, 135-141Google ScholarPubMed
18Kriz, W. (1969) Lymphatic vessels of mammalian kidneys. Verhandlungen der Anatomischen Gesellschaft 63, 25-32Google Scholar
19Lee, H. et al. (2011) Expression of lymphatic endothelium-specific hyaluronan receptor LYVE-1 in the developing mouse kidney. Cell and Tissue Research 343, 429-444Google Scholar
20Tanabe, M. et al. (2012) Development of lymphatic vasculature and morphological characterization in rat kidney. Clinical and Experimental Nephrology 16, 833-842CrossRefGoogle ScholarPubMed
21Matsui, K. et al. (2003) Lymphatic microvessels in the rat remnant kidney model of renal fibrosis: aminopeptidase p and podoplanin are discriminatory markers for endothelial cells of blood and lymphatic vessels. Journal of the American Society of Nephrology 14, 1981-1989Google Scholar
22Voss, M. et al. (2009) The lymphatic system and its specific growth factor vascular endothelial growth factor C in kidney tissue and in renal cell carcinoma. BJU International 104, 94-99CrossRefGoogle ScholarPubMed
23Sakamoto, I. et al. (2009) Lymphatic vessels develop during tubulointerstitial fibrosis. Kidney International 75, 828-838Google Scholar
24Ishikawa, Y. et al. (2006) The human renal lymphatics under normal and pathological conditions. Histopathology 49, 265-273Google Scholar
25Bonsib, S. M. (2006) Renal lymphatics, and lymphatic involvement in sinus vein invasive (pT3b) clear cell renal cell carcinoma: a study of 40 cases. Modern Pathology 19, 746-753CrossRefGoogle ScholarPubMed
26Holmes, M. J., O'Morchoe, P. J. and O'Morchoe, C. C. (1977) Morphology of the intrarenal lymphatic system. Capsular and hilar communications. The American Journal of Anatomy 149, 333-351Google Scholar
27Bell, R. D. et al. (1968) Renal lymphatics: the internal distribution. Nephron 5, 454-463Google Scholar
28Clark, R. L. and Cuttino, J. T. Jr. (1977) Microradiographic studies of renal lymphatics. Radiology 124, 307-311Google Scholar
29Hirakawa, S. (2011) Regulation of pathological lymphangiogenesis requires factors distinct from those governing physiological lymphangiogenesis. Journal of Dermatological Science 61, 85-93Google Scholar
30Otsuki, Y., Magari, S. and Sugimoto, O. (1986) Lymphatic capillaries in rabbit ovaries during ovulation: an ultrastructural study. Lymphology 19, 55-64Google Scholar
31Martínez-Corral, I. et al. (2012) In vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis. Proceedings of the National Academy of Sciences of the United States of America 109, 6223-8Google Scholar
32Zheng, W., Aspelund, A., Alitalo, K. (2014) Lymphangiogenic factors, mechanisms, and applications. The Journal of Clinical Investigation 124, 878-87Google Scholar
33Marino, D. et al. (2013) Activation of the epidermal growth factor receptor promotes lymphangiogenesis in the skin. Journal of Dermatological Science 71, 184-194Google Scholar
34Lee, A. S. et al. (2011) Erythropoietin induces lymph node lymphangiogenesis and lymph node tumor metastasis. Cancer Research 71, 4506-4517Google Scholar
35Karkkainen, M. J. et al. (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunology 5, 74-80Google Scholar
36Benest, AV. et al. (2008) VEGF-C induced angiogenesis preferentially occurs at a distance from lymphangiogenesis. Cardiovascular Research 78, 315-323Google Scholar
37Rissanen, TT. et al. (2003) VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circulation Research 92, 1098-106Google Scholar
38Alitalo, K. (2011) The lymphatic vasculature in disease. Nature Medicine 17, 1371-1380Google Scholar
39Card, CM., Yu, SS., Swartz, MA. (2014) Emerging roles of lymphatic endothelium in regulating adaptive immunity. The Journal of Clinical Investigation 124, 943-52CrossRefGoogle ScholarPubMed
40Johnson, L. A. and Jackson, D. G. (2010) Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key regulator of integrin-mediated dendritic cell transmigration. International Immunology 22, 839-849Google Scholar
41Kriehuber, E. et al. (2001) Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. The Journal of Experimental Medicine 194, 797-808Google Scholar
42Randolph, G. J., Angeli, V. and Swartz, M. A. (2005) Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nature Reviews Immunology 5, 617-628CrossRefGoogle ScholarPubMed
43Haessler, U. et al. (2011) Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19. Proceedings of the National Academy of Sciences of the United States of America 108, 5614-5619Google Scholar
44Wick, N. et al. (2008) Lymphatic precollectors contain a novel, specialized subpopulation of podoplanin low, CCL27-expressing lymphatic endothelial cells. The American Journal of Pathology 173, 1202-1209Google Scholar
45Kerjaschki, D. et al. (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. Journal of the American Society of Nephrology 15, 603-612Google Scholar
46Johnson, LA. et al. (2006) An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. Journal of Experimental Medicine 203, 2763-2777Google Scholar
47Neusser, M. A. et al. (2010) The chemokine receptor CXCR7 is expressed on lymphatic endothelial cells during renal allograft rejection. Kidney International 77, 801-808Google Scholar
48Mancardi, S. et al. (2003) Evidence of CXC, CC and C chemokine production by lymphatic endothelial cells. Immunology 108, 523-530Google Scholar
49Gardner, L. et al. (2004) The human duffy antigen binds selected inflammatory but not homeostatic chemokines. Biochemical and Biophysical Research Communications 321, 306-312Google Scholar
50Pruenster, M. et al. (2009) The duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nature Immunology 10, 101-108Google Scholar
51Akiyama, T. et al. (2008) Immunohistochemical detection of sphingosine-1-phosphate receptor 1 in vascular and lymphatic endothelial cells. Journal of Molecular Histology 39, 527-533Google Scholar
52Pham, T. H. et al. (2010) Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. The Journal of Experimental Medicine 207, 17-27Google Scholar
53Aoyagi, T. et al. (2012) The role of sphingosine-1-phosphate in breast cancer tumor-induced lymphangiogenesis. Lymphatic Research and Biology 10, 97-106Google Scholar
54Yoon, C. M. et al. (2008) Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways. Blood 112, 1129-1138Google Scholar
55Yin, N. et al. (2011) Targeting lymphangiogenesis after islet transplantation prolongs islet al.lograft survival. Transplantation 92, 25-30Google Scholar
56Kim, J. Y. et al. (2005) Effect of FTY720 on chronic cyclosporine nephropathy in rats. Transplantation 80, 1323-1330Google Scholar
57Long, D. A. and Price, K. L. (2009) Sphingosine kinase-1: a potential mediator of renal fibrosis. Kidney International 76, 815-817Google Scholar
58Kramer, S. et al. (2009) The lymphocyte migration inhibitor FTY720 attenuates experimental hypertensive nephropathy. American Journal of Physiology. Renal Physiology 297, F218-F227Google Scholar
59Loffredo, S. et al. (2014) Immune cells as a source and target of angiogenic and lymphangiogenic factors. Chemical Immunology and Allergy 99, 15-36Google Scholar
60Angeli, V. et al. (2006) B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24, 203-215Google Scholar
61Conrady, C. D. et al. (2012) CD8+ T cells suppress viral replication in the cornea but contribute to VEGF-C-induced lymphatic vessel genesis. Journal of Immunology 189, 425-432Google Scholar
62Kataru, RP. et al. (2009) Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113, 5650-5659Google Scholar
63Tan, K. W. et al. (2013) Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D. Blood 122, 3666-3677Google Scholar
64Ran, S. and Montgomery, K. E. (2012) Macrophage-mediated lymphangiogenesis: the emerging role of macrophages as lymphatic endothelial progenitors. Cancers 4, 618-657Google Scholar
65Hall, K. L. et al. (2012) New model of macrophage acquisition of the lymphatic endothelial phenotype. PLoS ONE 7, e31794Google Scholar
66Adair, A. et al. (2007) Peritubular capillary rarefaction and lymphangiogenesis in chronic allograft failure. Transplantation 83, 1542-1550Google Scholar
67Lee, A. S. et al. (2013) Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction. Kidney International 83, 50-62Google Scholar
68Poosti, F. et al. (2012) Targeted inhibition of renal rho kinase reduces macrophage infiltration and lymphangiogenesis in acute renal allograft rejection. European Journal of Pharmacology 694, 111-119Google Scholar
69Suzuki, Y. et al. (2012) Transforming growth factor-beta induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction. Kidney International 81, 865-879Google Scholar
70Yazdani, S. et al. (2012) Proteinuria triggers renal lymphangiogenesis prior to the development of interstitial fibrosis. PLoS ONE 7, e50209Google Scholar
71Heller, F. et al. (2007) The contribution of B cells to renal interstitial inflammation. The American Journal of Pathology 170, 457-468Google Scholar
72Huang, Y. et al. (2014) Identification of novel genes associated with renal tertiary lymphoid organ formation in aging mice. PLoS ONE 9, e91850Google Scholar
73Carragher, D. M., Rangel-Moreno, J. and Randall, T. D. (2008) Ectopic lymphoid tissues and local immunity. Seminars in Immunology 20, 26-42Google Scholar
74Aloisi, F. and Pujol-Borrell, R. (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nature Reviews Immunology 6, 205-217Google Scholar
75Seeger, H., Bonani, M. and Segerer, S. (2012) The role of lymphatics in renal inflammation. Nephrology, Dialysis, Transplantation 27, 2634-2641Google Scholar
76Wick, G. et al. (2013) The immunology of fibrosis. Annual Review of Immunology 31, 107-135Google Scholar
77Zampell, J. C. et al. (2012) CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis. PLoS ONE 7, e49940Google Scholar
78El-Chemaly, S. et al. (2009) Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms. Proceedings of the National Academy of Sciences of the United States of America 106, 3958-3963Google Scholar
79Meinecke, A. K. et al. (2012) Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis. Blood 119, 5931-5942Google Scholar
80Sakai, N. et al. (2006) Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proceedings of the National Academy of Sciences of the United States of America 103, 14098-14103Google Scholar
81Oka, M. et al. (2008) Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood 111, 4571-4579Google Scholar
82Kinashi, H. et al. (2013) TGF-β1 promotes lymphangiogenesis during peritoneal fibrosis. Journal of American Society of Nephrology 24, 1627-1642Google Scholar
83James, JM., Nalbandian, A. and Mukouyama, YS. (2013) TGFβ signaling is required for sprouting lymphangiogenesis during lymphatic network development in the skin. Development 140, 3903-3914CrossRefGoogle ScholarPubMed
84Podgrabinska, S. et al. (2002) Molecular characterization of lymphatic endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 99, 16069-16074Google Scholar
85Malhotra, D. et al. (2012) Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nature Immunology 13, 499-510Google Scholar
86Zhao, T. et al. (2014) Vascular endothelial growth factor-C: its unrevealed role in fibrogenesis. American Journal of Physiology Heart and Circulatory Physiology 306, H789-H796Google Scholar
87Ling, S. et al. (2009) Crucial role of corneal lymphangiogenesis for allograft rejection in alkali-burned cornea bed. Clinical and Experimental Ophthalmology 37, 874-883CrossRefGoogle ScholarPubMed
88Tang, X. L. et al. (2010) Blocking neuropilin-2 enhances corneal allograft survival by selectively inhibiting lymphangiogenesis on vascularized beds. Molecular Vision 16, 2354-2361Google Scholar
89Dietrich, T. et al. (2010) Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. Journal of Immunology (Baltimore, MD: 1950) 184, 535-539Google Scholar
90Uehara, H. et al. (2013) Dual suppression of hemangiogenesis and lymphangiogenesis by splice-shifting morpholinos targeting vascular endothelial growth factor receptor 2 (KDR). FASEB Journal 27, 76-85Google Scholar
91Zheng, Y., Lin, H. and Ling, S. (2011) Clinicopathological correlation analysis of (lymph) angiogenesis and corneal graft rejection. Molecular Vision 17, 1694-1700Google Scholar
92Geissler, H. J. et al. (2006) First year changes of myocardial lymphatic endothelial markers in heart transplant recipients. European Journal of Cardio-Thoracic Surgery 29, 767-771Google Scholar
93Dashkevich, A. et al. (2010) Lymph angiogenesis after lung transplantation and relation to acute organ rejection in humans. The Annals of Thoracic Surgery 90, 406-411Google Scholar
94Stuht, S. et al. (2007) Lymphatic neoangiogenesis in human renal allografts: results from sequential protocol biopsies. American Journal of Transplantation 7, 377-384Google Scholar
95Nykanen, A. I. 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, 1413-1422Google Scholar
96Vass, D. G. et al. (2012) Inflammatory lymphangiogenesis in a rat transplant model of interstitial fibrosis and tubular atrophy. Transplant International 25, 792-800Google Scholar
97Rienstra, H. et al. (2010) Differential expression of proteoglycans in tissue remodeling and lymphangiogenesis after experimental renal transplantation in rats. PLoS ONE 5, e9095Google Scholar
98Palin, N. K., Savikko, J. and Koskinen, P. K. (2013) Sirolimus inhibits lymphangiogenesis in rat renal allografts, a novel mechanism to prevent chronic kidney allograft injury. Transplant International 26, 195-205Google Scholar
99Huber, S. et al. (2007) Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis. Kidney International 71, 771-777Google Scholar
100Ersoy, A. and Koca, N. (2012) Everolimus-induced lymphedema in a renal transplant recipient: a case report. Experimental and Clinical Transplantation 10, 296-298Google Scholar
101Mendez, U. et al. (2012) Functional recovery of fluid drainage precedes lymphangiogenesis in acute murine foreleg lymphedema. American Journal of Physiology. Heart and Circulatory Physiology 302, H2250-H2256Google Scholar
102Rodriguez-Iturbe, B., Herrera-Acosta, J. and Johnson, R. J. (2002) Interstitial inflammation, sodium retention, and the pathogenesis of nephrotic edema: a unifying hypothesis. Kidney International 62, 1379-1384Google Scholar
103Zhang, T. et al. (2008) Disturbance of lymph circulation develops renal fibrosis in rats with or without contralateral nephrectomy. Nephrology (Carlton, VIC) 13, 128-138Google Scholar
104Zhang, T. et al. (2009) Functional, histological and biochemical consequences of renal lymph disorder in mononephrectomized rats. Journal of Nephrology 22, 109-116Google Scholar
105Choi, I. et al. (2012) 9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema. Circulation 125, 872-882Google Scholar
106Szuba, A. et al. (2002) Therapeutic lymphangiogenesis with human tecombinant VEGF-C. FASEB Journal 16, 1985-1987Google Scholar
107Cheung, L. et al. (2006) An rxperimental model for the dtudy of lymphedema and its tesponse to yherapeutic lymphangiogenesis. Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy 20, 363-370Google Scholar
108Planas-Paz, L. et al. (2012) Mechanoinduction of lymph vessel expansion. EMBO Journal 31, 788-804Google Scholar
109Machnik, A. et al. (2009) Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nature Medicine 15, 545-552Google Scholar
110Machnik, A. et al. (2010) Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats. Hypertension 55, 755-761Google Scholar
111Wiig, H. et al. (2013) Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. Journal of Clinical Investigation 123, 2803-2815Google Scholar
112Slagman, M. C. et al. (2012) Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects. Nephrology, Dialysis, Transplantation 27, 978-982Google Scholar
113Lely, A. T. et al. (2013) Circulating lymphangiogenic factors in preeclampsia. Hypertension in Pregnancy 32, 42-49Google Scholar
114Toering, T. J., Navis, G. and Lely, A. T. (2013) The role of the VEGF-C signaling pathway in preeclampsia? Journal of Reproductive Immunology 100, 128Google Scholar
115Mono, JA. et al. (2014) Role of chemokines in proteinuric kidney disorders.Expert Reviews in Molecular Medicine, 16, e3Google Scholar
116Liersch, R. et al. (2012) Analysis of a novel highly metastatic melanoma cell line identifies osteopontin as a new lymphangiogenic factor. International Journal of Oncology 41, 1455-1463Google Scholar
117Moriguchi, P. et al. (2005) Lymphatic system changes in diabetes mellitus: role of insulin and hyperglycemia. Diabetes/Metabolism Research and Reviews 21, 150-157Google Scholar
118Haemmerle, M. et al. (2013) Enhanced lymph vessel density, remodeling, and inflammation are reflected by gene expression signatures in dermal lymphatic endothelial cells in Type 2 diabetes. Diabetes 62, 2509-2529Google Scholar
119Kivela, R. et al. (2007) Effects of acute exercise, exercise training, and diabetes on the expression of lymphangiogenic growth factors and lymphatic vessels in skeletal muscle. American Journal of Physiology. Heart and Circulatory Physiology 293, H2573-H2579Google Scholar
120Yin, N. et al. (2011) Lymphangiogenesis is required for pancreatic islet inflammation and diabetes. PLoS ONE 6, e28023Google Scholar
121Uchiyama, T. et al. (2013) Altered dynamics in the renal lymphatic circulation of Type 1 and Type 2 diabetic mice. Acta Histochemica et Cytochemica 46, 97-104Google Scholar
122Karaman, S., and Detmar, M. (2014) Mechanisms of lymphatic metastasis. The Journal of Clinical Investigation 124, 922-928Google Scholar
123Lin, J. et al. (2005) Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Research 65, 6901-6909Google Scholar
124Bierer, S. et al. (2008) Lymphangiogenesis in kidney cancer: expression of VEGF-C, VEGF-D and VEGFR-3 in clear cell and papillary renal cell carcinoma. Oncology Reports 20, 721-725Google Scholar
125Horiguchi, A. et al. (2008) Intratumoral lymphatics and lymphatic invasion are associated with tumor aggressiveness and poor prognosis in renal cell carcinoma. Urology 71, 928-932Google Scholar
126Ozardili, I. et al. (2012) Correlation between lymphangiogenesis and clinicopathological parameters in renal cell carcinoma. Singapore Medical Journal 53, 332-335Google Scholar
127Debinski, P. et al. (2013) The clinical significance of lymphangiogenesis in renal cell carcinoma. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research 19, 606-611Google Scholar
128Baldewijns, M. M. et al. (2009) A low frequency of lymph node metastasis in clear-cell renal cell carcinoma is related to low lymphangiogenic Activity. BJU International 103, 1626-1631Google Scholar
129Iwata, T. et al. (2008) Lymphangiogenesis and angiogenesis in conventional renal cell carcinoma: association with vascular endothelial growth factors A to D immunohistochemistry. Urology 71, 749-754Google Scholar
130Ishikawa, Y. et al. (2007) Significance of lymphatic invasion and proliferation on regional lymph node metastasis in renal cell carcinoma. American Journal of Clinical Pathology 128, 198-207Google Scholar
131Eisenberg, M. S. et al. (2013) Association of microvascular and capillary-lymphatic invasion with outcome in patients with renal cell carcinoma. The Journal of Urology 190, 37-43Google Scholar
132Kroeger, N. et al. (2012) Clinical, molecular, and genetic correlates of lymphatic spread in clear cell renal cell carcinoma. European Urology 61, 888-895Google Scholar