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Adrenomedullin in lymphangiogenesis: from development to disease

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Abstract

Over the past decade, we have begun to appreciate that the lymphatic vascular system does more than simply return plasma back into the circulatory system and, in fact, contributes to a wide variety of normal and disease states. For this reason, much research has been devoted to understanding how lymphatic vessels form and function, with a particular interest in which molecules contribute to lymphatic vessel growth and maintenance. In the following review, we focus on a potent lymphangiogenic factor, adrenomedullin, and its known roles in lymphangiogenesis, lymphatic function, and human lymphatic disease. As one of the first, pharmacologically tractable G protein-coupled receptor pathways characterized in lymphatic endothelial cells, the continued study of adrenomedullin effects on the lymphatic system may open new avenues for the modulation of lymphatic growth and function in a variety of lymphatic-related diseases that currently have few treatments.

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References

  1. Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140(4):460–476. doi:10.1016/j.cell.2010.01.045

    Article  CAS  PubMed  Google Scholar 

  2. Zheng W, Aspelund A, Alitalo K (2014) Lymphangiogenic factors, mechanisms, and applications. J Clin Invest 124(3):878–887. doi:10.1172/JCI71603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kerjaschki D (2014) The lymphatic vasculature revisited. J Clin Invest 124(3):874–877. doi:10.1172/JCI74854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mortimer PS, Rockson SG (2014) New developments in clinical aspects of lymphatic disease. J Clin Invest 124(3):915–921. doi:10.1172/JCI71608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Warren AG, Brorson H, Borud LJ, Slavin SA (2007) Lymphedema: a comprehensive review. Ann Plast Surg 59(4):464–472. doi:10.1097/01.sap.0000257149.42922.7e

    Article  CAS  PubMed  Google Scholar 

  6. Wiig H, Schroder A, Neuhofer W, Jantsch J, Kopp C, Karlsen TV, Boschmann M, Goss J, Bry M, Rakova N, Dahlmann A, Brenner S, Tenstad O, Nurmi H, Mervaala E, Wagner H, Beck FX, Muller DN, Kerjaschki D, Luft FC, Harrison DG, Alitalo K, Titze J (2013) Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. J Clin Invest 123(7):2803–2815. doi:10.1172/JCI60113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Harvey NL, Srinivasan RS, Dillard ME, Johnson NC, Witte MH, Boyd K, Sleeman MW, Oliver G (2005) Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat Genet 37(10):1072–1081

    Article  CAS  PubMed  Google Scholar 

  8. Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM (2002) International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev 54(2):233–246

    Article  CAS  PubMed  Google Scholar 

  9. Lenhart PM, Caron KM (2012) Adrenomedullin and pregnancy: perspectives from animal models to humans. Trends Endocrinol Metab 23(10):524–532. doi:10.1016/j.tem.2012.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Muff R, Born W, Lutz TA, Fischer JA (2004) Biological importance of the peptides of the calcitonin family as revealed by disruption and transfer of corresponding genes. Peptides 25(11):2027–2038. doi:10.1016/j.peptides.2004.08.007

    Article  CAS  PubMed  Google Scholar 

  11. Smith DM, Coppock HA, Withers DJ, Owji AA, Hay DL, Choksi TP, Chakravarty P, Legon S, Poyner DR (2002) Adrenomedullin: receptor and signal transduction. Biochem Soc Trans 30(4):432–437

    Article  CAS  PubMed  Google Scholar 

  12. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393(6683):333–339

    Article  CAS  PubMed  Google Scholar 

  13. Gibbons C, Dackor R, Dunworth W, Fritz-Six K, Caron KM (2007) Receptor activity-modifying proteins: RAMPing up adrenomedullin signaling. Mol Endocrinol 21(4):783–796. doi:10.1210/me.2006-0156

    Article  CAS  PubMed  Google Scholar 

  14. Fritz-Six KL, Dunworth WP, Li M, Caron KM (2008) Adrenomedullin signaling is necessary for murine lymphatic vascular development. J Clin Invest 118(1):40–50. doi:10.1172/JCI33302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hay DL, Walker CS, Poyner DR (2011) Adrenomedullin and calcitonin gene-related peptide receptors in endocrine-related cancers: opportunities and challenges. Endocr Relat Cancer 18(1):C1–14. doi:10.1677/ERC-10-0244

    Article  CAS  PubMed  Google Scholar 

  16. Kapas S, Catt KJ, Clark AJ (1995) Cloning and expression of cDNA encoding a rat adrenomedullin receptor. J Biol Chem 270(43):25344–25347

    Article  CAS  PubMed  Google Scholar 

  17. Kapas S, Clark AJ (1995) Identification of an orphan receptor gene as a type 1 calcitonin gene-related peptide receptor. Biochem Biophys Res Commun 217(3):832–838. doi:10.1006/bbrc.1995.2847

    Article  CAS  PubMed  Google Scholar 

  18. Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F (2005) The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem 280(42):35760–35766

    Article  CAS  PubMed  Google Scholar 

  19. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ (2006) A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med 203(9):2201–2213. doi:10.1084/jem.20052144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ikeda Y, Kumagai H, Skach A, Sato M, Yanagisawa M (2013) Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior. Cell 155(6):1323–1336. doi:10.1016/j.cell.2013.10.052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sierro F, Biben C, Martinez-Munoz L, Mellado M, Ransohoff RM, Li M, Woehl B, Leung H, Groom J, Batten M, Harvey RP, Martinez AC, Mackay CR, Mackay F (2007) Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci USA 104(37):14759–14764. doi:10.1073/pnas.0702229104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Autelitano DJ, Tang F (1999) Co-expression of prepro-adrenomedullin with a putative adrenomedullin receptor gene in vascular smooth muscle. Clin Sci (Lond) 96(5):493–498

    Article  CAS  Google Scholar 

  23. Chakravarty P, Suthar TP, Coppock HA, Nicholl CG, Bloom SR, Legon S, Smith DM (2000) CGRP and adrenomedullin binding correlates with transcript levels for calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) in rat tissues. Br J Pharmacol 130(1):189–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ladoux A, Frelin C (2000) Coordinated Up-regulation by hypoxia of adrenomedullin and one of its putative receptors (RDC-1) in cells of the rat blood-brain barrier. J Biol Chem 275(51):39914–39919

    Article  CAS  PubMed  Google Scholar 

  25. Klein KR, Karpinich NO, Espenschied ST, Willcockson HH, Dunworth WP, Hoopes SL, Kushner EJ, Bautch VL, Caron KM (2014) Decoy receptor CXCR7 modulates adrenomedullin-mediated cardiac and lymphatic vascular development. Dev Cell 30(5):528–540. doi:10.1016/j.devcel.2014.07.012

    Article  CAS  PubMed  Google Scholar 

  26. Betterman KL, Harvey NL (2014) Decoys and cardiovascular development: CXCR7 and regulation of adrenomedullin signaling. dev cell 30(5):490–491. doi:10.1016/j.devcel.2014.08.021

    Article  CAS  PubMed  Google Scholar 

  27. Karpinich NO, Hoopes SL, Kechele DO, Lenhart PM, Caron KM (2011) Adrenomedullin function in vascular endothelial cells: insights from genetic mouse models. Curr Hypertens Rev 7(4):228–239. doi:10.2174/157340211799304761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Di Iorio R, Marinoni E, Letizia C, Alo P, Villaccio B, Cosmi EV (1998) Adrenomedullin, a new vasoactive peptide, is increased in preeclampsia. Hypertension 32(4):758–763

    Article  CAS  PubMed  Google Scholar 

  29. Nuki C, Kawasaki H, Kitamura K, Takenaga M, Kangawa K, Eto T, Wada A (1993) Vasodilator effect of adrenomedullin and calcitonin gene-related peptide receptors in rat mesenteric vascular beds. Biochem Biophys Res Commun 196(1):245–251. doi:10.1006/bbrc.1993.2241

    Article  CAS  PubMed  Google Scholar 

  30. Hinson JP, Kapas S, Smith DM (2000) Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 21(2):138–167

    CAS  PubMed  Google Scholar 

  31. Kataoka Y, Miyazaki S, Yasuda S, Nagaya N, Noguchi T, Yamada N, Morii I, Kawamura A, Doi K, Miyatake K, Tomoike H, Kangawa K (2010) The first clinical pilot study of intravenous adrenomedullin administration in patients with acute myocardial infarction. J Cardiovasc Pharmacol 56(4):413–419. doi:10.1097/FJC.0b013e3181f15b45

  32. Hagerling R, Pollmann C, Andreas M, Schmidt C, Nurmi H, Adams RH, Alitalo K, Andresen V, Schulte-Merker S, Kiefer F (2013) A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J 32(5):629–644. doi:10.1038/emboj.2012.340

    Article  PubMed  PubMed Central  Google Scholar 

  33. Yang Y, Oliver G (2014) Development of the mammalian lymphatic vasculature. J Clin Invest 124(3):888–897. doi:10.1172/JCI71609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, Jackson DG, Oliver G (2002) An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 21(7):1505–1513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98(6):769–778

    Article  CAS  PubMed  Google Scholar 

  36. Alitalo K, Tammela T, Petrova TV (2005) Lymphangiogenesis in development and human disease. Nature 438(7070):946–953. doi:10.1038/nature04480

    Article  CAS  PubMed  Google Scholar 

  37. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5(1):74–80. doi:10.1038/ni1013

    Article  CAS  PubMed  Google Scholar 

  38. 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 (2001) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7(2):199–205

    Article  CAS  PubMed  Google Scholar 

  39. Dackor RT, Fritz-Six K, Dunworth WP, Gibbons CL, Smithies O, Caron KM (2006) Hydrops fetalis, cardiovascular defects, and embryonic lethality in mice lacking the calcitonin receptor-like receptor gene. Mol Cell Biol 26(7):2511–2518. doi:10.1128/MCB.26.7.2511-2518.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Caron KM, Smithies O (2001) Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional Adrenomedullin gene. Proc Natl Acad Sci USA 98(2):615–619. doi:10.1073/pnas.021548898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shindo T, Kurihara Y, Nishimatsu H, Moriyama N, Kakoki M, Wang Y, Imai Y, Ebihara A, Kuwaki T, Ju KH, Minamino N, Kangawa K, Ishikawa T, Fukuda M, Akimoto Y, Kawakami H, Imai T, Morita H, Yazaki Y, Nagai R, Hirata Y, Kurihara H (2001) Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene. Circulation 104(16):1964–1971

    Article  CAS  PubMed  Google Scholar 

  42. Shimosawa T, Shibagaki Y, Ishibashi K, Kitamura K, Kangawa K, Kato S, Ando K, Fujita T (2002) Adrenomedullin, an endogenous peptide, counteracts cardiovascular damage. Circulation 105(1):106–111

    Article  CAS  PubMed  Google Scholar 

  43. Ichikawa-Shindo Y, Sakurai T, Kamiyoshi A, Kawate H, Iinuma N, Yoshizawa T, Koyama T, Fukuchi J, Iimuro S, Moriyama N, Kawakami H, Murata T, Kangawa K, Nagai R, Shindo T (2008) The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity. J Clin Invest 118(1):29–39. doi:10.1172/JCI33022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dackor R, Fritz-Six K, Smithies O, Caron K (2007) Receptor activity-modifying proteins 2 and 3 have distinct physiological functions from embryogenesis to old age. J Biol Chem 282(25):18094–18099. doi:10.1074/jbc.M703544200

    Article  CAS  PubMed  Google Scholar 

  45. Czyzyk TA, Ning Y, Hsu MS, Peng B, Mains RE, Eipper BA, Pintar JE (2005) Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse. Dev Biol 287(2):301–313

    Article  CAS  PubMed  Google Scholar 

  46. Kisanuki YY, Hammer RE, Miyazaki J, Williams SC, Richardson JA, Yanagisawa M (2001) Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev Biol 230(2):230–242

    Article  CAS  PubMed  Google Scholar 

  47. Eklund L, Bry M, Alitalo K (2013) Mouse models for studying angiogenesis and lymphangiogenesis in cancer. Mol Oncol 7(2):259–282. doi:10.1016/j.molonc.2013.02.007

    Article  CAS  PubMed  Google Scholar 

  48. Tammela T, Saaristo A, Lohela M, Morisada T, Tornberg J, Norrmen C, Oike Y, Pajusola K, Thurston G, Suda T, Yla-Herttuala S, Alitalo K (2005) Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 105(12):4642–4648. doi:10.1182/blood-2004-08-3327

    Article  CAS  PubMed  Google Scholar 

  49. Morisada T, Oike Y, Yamada Y, Urano T, Akao M, Kubota Y, Maekawa H, Kimura Y, Ohmura M, Miyamoto T, Nozawa S, Koh GY, Alitalo K, Suda T (2005) Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 105(12):4649–4656

    Article  CAS  PubMed  Google Scholar 

  50. Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, Samokhvalov IM, Oliver G (2007) Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev 21(19):2422–2432. doi:10.1101/gad.1588407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen L, Mupo A, Huynh T, Cioffi S, Woods M, Jin C, McKeehan W, Thompson-Snipes L, Baldini A, Illingworth E (2010) Tbx1 regulates Vegfr3 and is required for lymphatic vessel development. J Cell Biol 189(3):417–424. doi:10.1083/jcb.200912037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Nikitenko LL, Shimosawa T, Henderson S, Makinen T, Shimosawa H, Qureshi U, Pedley B, Rees MC, Fujita T, Boshoff C (2013) Adrenomedullin haploinsufficiency predisposes to secondary lymphedema. J Invest Dermatol. doi:10.1038/jid.2013.47

    PubMed  PubMed Central  Google Scholar 

  53. Jin D, Otani K, Yamahara K, Ikeda T, Nagaya N, Kangawa K (2011) Adrenomedullin reduces expression of adhesion molecules on lymphatic endothelial cells. Regul Pept 166(1–3):21–27. doi:10.1016/j.regpep.2010.08.003

    Article  CAS  PubMed  Google Scholar 

  54. Dunworth WP, Fritz-Six KL, Caron KM (2008) Adrenomedullin stabilizes the lymphatic endothelial barrier in vitro and in vivo. Peptides 29(12):2243–2249. doi:10.1016/j.peptides.2008.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cullen VC, Mackarel AJ, Hislip SJ, O’Connor CM, Keenan AK (2000) Investigation of vascular endothelial growth factor effects on pulmonary endothelial monolayer permeability and neutrophil transmigration. Gen Pharmacol 35(3):149–157

    Article  CAS  PubMed  Google Scholar 

  56. Kahn ML (2008) Blood is thicker than lymph. J Clin Invest 118(1):23–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Nicoli S, Tobia C, Gualandi L, De Sena G, Presta M (2008) Calcitonin receptor-like receptor guides arterial differentiation in zebrafish. Blood 111(10):4965–4972

    Article  CAS  PubMed  Google Scholar 

  58. Ribatti D, Nico B, Spinazzi R, Vacca A, Nussdorfer GG (2005) The role of adrenomedullin in angiogenesis. Peptides 26(9):1670–1675

    Article  CAS  PubMed  Google Scholar 

  59. Moissoglu K, Majumdar R, Parent CA (2014) Cell migration: sinking in a gradient. Curr Biol 24(1):R23–R25. doi:10.1016/j.cub.2013.10.075

    Article  CAS  PubMed  Google Scholar 

  60. Venkiteswaran G, Lewellis SW, Wang J, Reynolds E, Nicholson C, Knaut H (2013) Generation and dynamics of an endogenous, self-generated signaling gradient across a migrating tissue. Cell 155(3):674–687. doi:10.1016/j.cell.2013.09.046

    Article  CAS  PubMed  Google Scholar 

  61. Yu S, Crawford D, Tsuchihashi T, Behrens TW, Srivastava D (2011) The chemokine receptor CXCR7 functions to regulate cardiac valve remodeling. Dev Dyn 240(2):384–393. doi:10.1002/dvdy.22549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gerrits H, van Ingen Schenau DS, Bakker NE, van Disseldorp AJ, Strik A, Hermens LS, Koenen TB, Krajnc-Franken MA, Gossen JA (2008) Early postnatal lethality and cardiovascular defects in CXCR7-deficient mice. Genesis 46(5):235–245. doi:10.1002/dvg.20387

    Article  CAS  PubMed  Google Scholar 

  63. Wetzel-Strong SE, Li M, Klein KR, Nishikimi T, Caron KM (2013) Epicardial-derived adrenomedullin drives cardiac hyperplasia during embryogenesis. Dev Dyn 243(2):243–256. doi:10.1002/dvdy.24065

    Article  Google Scholar 

  64. Hoopes SL, Willcockson HH, Caron KM (2012) Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice. PLoS One 7(9):e45261. doi:10.1371/journal.pone.0045261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Regenfuss B, Bock F, Parthasarathy A, Cursiefen C (2008) Corneal (lymph)angiogenesis—from bedside to bench and back: a tribute to Judah Folkman. Lymphat Res Biol 6(3–4):191–201. doi:10.1089/lrb.2008.6348

    Article  PubMed  Google Scholar 

  66. Park DY, Lee J, Park I, Choi D, Lee S, Song S, Hwang Y, Hong KY, Nakaoka Y, Makinen T, Kim P, Alitalo K, Hong YK, Koh GY (2014) Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity. J Clin Invest 124(9):3960–3974. doi:10.1172/JCI75392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aspelund A, Tammela T, Antila S, Nurmi H, Leppanen VM, Zarkada G, Stanczuk L, Francois M, Makinen T, Saharinen P, Immonen I, Alitalo K (2014) The Schlemm’s canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. J Clin Invest 124(9):3975–3986. doi:10.1172/JCI75395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Karpinich NO, Caron KM (2014) Schlemm’s canal: more than meets the eye, lymphatics in disguise. J Clin Invest 124(9):3701–3703. doi:10.1172/JCI77507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Brouillard P, Boon L, Vikkula M (2014) Genetics of lymphatic anomalies. J Clin Invest 124(3):898–904. doi:10.1172/JCI71614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Alitalo K (2011) The lymphatic vasculature in disease. Nat Med 17(11):1371–1380. doi:10.1038/nm.2545

    Article  CAS  PubMed  Google Scholar 

  71. Donker M, van Tienhoven G, Straver ME, Meijnen P, van de Velde CJ, Mansel RE, Cataliotti L, Westenberg AH, Klinkenbijl JH, Orzalesi L, Bouma WH, van der Mijle HC, Nieuwenhuijzen GA, Veltkamp SC, Slaets L, Duez NJ, de Graaf PW, van Dalen T, Marinelli A, Rijna H, Snoj M, Bundred NJ, Merkus JW, Belkacemi Y, Petignat P, Schinagl DA, Coens C, Messina CG, Bogaerts J, Rutgers EJ (2014) Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol 15(12):1303–1310. doi:10.1016/S1470-2045(14)70460-7

    Article  PubMed  PubMed Central  Google Scholar 

  72. McLaughlin SA, Wright MJ, Morris KT, Giron GL, Sampson MR, Brockway JP, Hurley KE, Riedel ER, Van Zee KJ (2008) Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J Clin Oncol 26(32):5213–5219. doi:10.1200/JCO.2008.16.3725

    Article  PubMed  PubMed Central  Google Scholar 

  73. Jin D, Harada K, Ohnishi S, Yamahara K, Kangawa K, Nagaya N (2008) Adrenomedullin induces lymphangiogenesis and ameliorates secondary lymphoedema. Cardiovasc Res 80(3):339–345. doi:10.1093/cvr/cvn228

    Article  CAS  PubMed  Google Scholar 

  74. Hirakawa S, Detmar M (2004) New insights into the biology and pathology of the cutaneous lymphatic system. J Dermatol Sci 35(1):1–8. doi:10.1016/j.jdermsci.2003.10.006

    Article  CAS  PubMed  Google Scholar 

  75. Tonnesen MG, Feng X, Clark RA (2000) Angiogenesis in wound healing. J Investig Dermatol Symp Proc 5(1):40–46. doi:10.1046/j.1087-0024.2000.00014.x

    Article  CAS  PubMed  Google Scholar 

  76. Zudaire E, Martinez A, Cuttitta F (2003) Adrenomedullin and cancer. Regul Pept 112(1–3):175–183

    Article  CAS  PubMed  Google Scholar 

  77. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 192(2):553–560. doi:10.1006/bbrc.1993.1451

    Article  CAS  PubMed  Google Scholar 

  78. Hu Z, Fan C, Livasy C, He X, Oh DS, Ewend MG, Carey LA, Subramanian S, West R, Ikpatt F, Olopade OI, van de Rijn M, Perou CM (2009) A compact VEGF signature associated with distant metastases and poor outcomes. BMC Med 7:9

    Article  PubMed  PubMed Central  Google Scholar 

  79. Park HC, Seong J, An JH, Kim J, Kim UJ, Lee BW (2005) Alteration of cancer pain-related signals by radiation: proteomic analysis in an animal model with cancer bone invasion. Int J Radiat Oncol Biol Phys 61(5):1523–1534. doi:10.1016/j.ijrobp.2004.12.070

    Article  CAS  PubMed  Google Scholar 

  80. Nikitenko LL, Fox SB, Kehoe S, Rees MC, Bicknell R (2006) Adrenomedullin and tumour angiogenesis. Br J Cancer 94(1):1–7. doi:10.1038/sj.bjc.6602832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG (2014) Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer 14(3):159–172. doi:10.1038/nrc3677

    Article  CAS  PubMed  Google Scholar 

  82. Ji RC (2014) Hypoxia and lymphangiogenesis in tumor microenvironment and metastasis. Cancer Lett 346(1):6–16. doi:10.1016/j.canlet.2013.12.001

    Article  CAS  PubMed  Google Scholar 

  83. Karpinich NO, Kechele DO, Espenschied ST, Willcockson HH, Fedoriw Y, Caron KM (2013) Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis. FASEB J 27(2):590–600. doi:10.1096/fj.12-214080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Huang TH, Chu TY (2013) Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer. Oncogene. doi:10.1038/onc.2013.335

    Google Scholar 

  85. Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ (2014) Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370(8):734–743. doi:10.1056/NEJMoa1309748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603. doi:10.1038/nrc2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bzowska M, Mezyk-Kopec R, Prochnicki T, Kulesza M, Klaus T, Bereta J (2013) Antibody-based antiangiogenic and antilymphangiogenic therapies to prevent tumor growth and progression. Acta Biochim Pol 60(3):263–275

    CAS  PubMed  Google Scholar 

  88. Berenguer-Daize C, Boudouresque F, Bastide C, Tounsi A, Benyahia Z, Acunzo J, Dussault N, Delfino C, Baeza N, Daniel L, Cayol M, Rossi D, El Battari A, Bertin D, Mabrouk K, Martin PM, Ouafik L (2013) Adrenomedullin blockade suppresses growth of human hormone-independent prostate tumor xenograft in mice. Clin Cancer Res 19(22):6138–6150. doi:10.1158/1078-0432.CCR-13-0691

    Article  CAS  PubMed  Google Scholar 

  89. Di Iorio R, Marinoni E, Scavo D, Letizia C, Cosmi EV (1997) Adrenomedullin in pregnancy. Lancet 349(9048):328

    Article  PubMed  Google Scholar 

  90. Lenhart PM, Nguyen T, Wise A, Caron KM, Herring AH, Stuebe AM (2014) Adrenomedullin signaling pathway polymorphisms and adverse pregnancy outcomes. Am J Perinatol 31(4):327–334. doi:10.1055/s-0033-1349345

    Article  PubMed  PubMed Central  Google Scholar 

  91. Li M, Schwerbrock NM, Lenhart PM, Fritz-Six KL, Kadmiel M, Christine KS, Kraus DM, Espenschied ST, Willcockson HH, Mack CP, Caron KM (2013) Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta. J Clin Invest 123(6):2408–2420. doi:10.1172/JCI67039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Matson BC, Corty RW, Karpinich NO, Murtha AP, Valdar W, Grotegut CA, Caron KM (2014) Midregional pro-adrenomedullin plasma concentrations are blunted in severe preeclampsia. Placenta 35(9):780–783. doi:10.1016/j.placenta.2014.07.003

    Article  CAS  PubMed  Google Scholar 

  93. Li M, Yee D, Magnuson TR, Smithies O, Caron KM (2006) Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice. J Clin Invest 116(10):2653–2662. doi:10.1172/JCI28462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rodero MP, Prignon A, Avril MF, Boitier F, Aractingi S, Khosrotehrani K (2013) Increase lymphangiogenesis in melanoma during pregnancy: correlation with the prolactin signalling pathway. J Eur Acad Dermatol Venereol 27(1):e144–e145. doi:10.1111/j.1468-3083.2012.04550.x

    Article  CAS  PubMed  Google Scholar 

  95. Khosrotehrani K, Nguyen Huu S, Prignon A, Avril MF, Boitier F, Oster M, Mortier L, Richard MA, Maubec E, Kerob D, Mansard S, Merheb C, Moguelet P, Nassar D, Guegan S, Aractingi S (2011) Pregnancy promotes melanoma metastasis through enhanced lymphangiogenesis. Am J Pathol 178(4):1870–1880. doi:10.1016/j.ajpath.2010.12.044

    Article  PubMed  PubMed Central  Google Scholar 

  96. Rogers PA, Donoghue JF, Girling JE (2008) Endometrial lymphangiogenesis. Placenta 29(Suppl A):S48–S54. doi:10.1016/j.placenta.2007.09.009

  97. Maybin JA, Battersby S, Hirani N, Nikitenko LL, Critchley HO, Jabbour HN (2011) The expression and regulation of adrenomedullin in the human endometrium: a candidate for endometrial repair. Endocrinology 152(7):2845–2856. doi:10.1210/en.2010-1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Nikitenko LL, MacKenzie IZ, Rees MC, Bicknell R (2000) Adrenomedullin is an autocrine regulator of endothelial growth in human endometrium. Mol Hum Reprod 6(9):811–819

    Article  CAS  PubMed  Google Scholar 

  99. Yurugi-Kobayashi T, Itoh H, Schroeder T, Nakano A, Narazaki G, Kita F, Yanagi K, Hiraoka-Kanie M, Inoue E, Ara T, Nagasawa T, Just U, Nakao K, Nishikawa S, Yamashita JK (2006) Adrenomedullin/cyclic AMP pathway induces Notch activation and differentiation of arterial endothelial cells from vascular progenitors. Arterioscler Thromb Vasc Biol 26(9):1977–1984

    Article  CAS  PubMed  Google Scholar 

  100. Guidolin D, Albertin G, Spinazzi R, Sorato E, Mascarin A, Cavallo D, Antonello M, Ribatti D (2008) Adrenomedullin stimulates angiogenic response in cultured human vascular endothelial cells: involvement of the vascular endothelial growth factor receptor 2. Peptides 29(11):2013–2023

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Sources of funding: UNC-CH University Cancer Research Innovation Award and U.S. National Institutes of Health, grants # HD060860, DK099156 to K.M.C. HL118932 to KRK.

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  1. Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, CB # 7545, 6312B MBRB, 111 Mason Farm Road, Chapel Hill, NC, 27599, USA

    Klara R. Klein & Kathleen M. Caron

  2. Department of Genetics, The University of North Carolina, Chapel Hill, NC, 27599, USA

    Kathleen M. Caron

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  1. Klara R. Klein
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  2. Kathleen M. Caron
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Correspondence to Kathleen M. Caron.

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Klein, K.R., Caron, K.M. Adrenomedullin in lymphangiogenesis: from development to disease. Cell. Mol. Life Sci. 72, 3115–3126 (2015). https://doi.org/10.1007/s00018-015-1921-3

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  • DOI: https://doi.org/10.1007/s00018-015-1921-3

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