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Cardiac lymphatics in health and disease

Nature Reviews Cardiology volume 16, pages 56–68 (2019)Cite this article

Subjects

Abstract

The lymphatic vasculature, which accompanies the blood vasculature in most organs, is indispensable in the maintenance of tissue fluid homeostasis, immune cell trafficking, and nutritional lipid uptake and transport, as well as in reverse cholesterol transport. In this Review, we discuss the physiological role of the lymphatic system in the heart in the maintenance of cardiac health and describe alterations in lymphatic structure and function that occur in cardiovascular pathology, including atherosclerosis and myocardial infarction. We also briefly discuss the role that immune cells might have in the regulation of lymphatic growth (lymphangiogenesis) and function. Finally, we provide examples of how the cardiac lymphatics can be targeted therapeutically to restore lymphatic drainage in the heart to limit myocardial oedema and chronic inflammation.

Key points

  • Cardiac lymphatics show a dynamic range of fluid uptake and transport that is linked to cardiac contractility and heart rate.

  • Cardiac lymphatics undergo substantial remodelling in several cardiovascular diseases, which can alter the lymphatic drainage capacity in the heart.

  • Insufficient lymphangiogenesis might contribute to the build-up of atherosclerotic lesions in large arteries owing to accumulation of both lipids and activated immune cells.

  • Immune cells contribute to the process of lymphatic remodelling by stimulating or inhibiting lymphangiogenesis.

  • Therapeutic stimulation of cardiac lymphangiogenesis after myocardial infarction leads to accelerated resolution of myocardial oedema and inflammation, promoting cardiac recovery.

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Fig. 1: Structure of the lymphatic vessel drainage pathway.
Fig. 2: Lymphatic vasculature in the heart.
Fig. 3: Lymphatic function versus oedema in the heart.
Fig. 4: Perivascular lymphatics in atherosclerosis.

References

  1. Shore, L. R. The lymphatic drainage of the human heart. J. Anat. 63, 291 (1929).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Patek, P. The morphology of the lymphatics of the mammalian heart. Am. J. Anat. 64, 203–249 (1939).

    Article  Google Scholar 

  3. Davis, K. L. et al. Effects of myocardial edema on the development of myocardial interstitial fibrosis. Microcirculation 7, 269–280 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Mehlhorn, U., Geissler, H. J., Laine, G. A. & Allen, S. J. Role of the cardiac lymph system in myocardial fluid balance. Eur. J. Cardiothorac. Surg. 20, 424–427 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Miller, A. J. The grossly invisible and generally ignored lymphatics of the mammalian heart. Med. Hypotheses 76, 604–606 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Alitalo, K., Tammela, T. & Petrova, T. V. Lymphangiogenesis in development and human disease. Nature 438, 946–953 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Petrova, T. V. & Koh, G. Y. Organ-specific lymphatic vasculature: from development to pathophysiology. J. Exp. Med. 215, 35–49 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bradham, R. R. & Parker, E. F. The cardiac lymphatics. Ann. Thorac. Surg. 15, 526–535 (1973).

    Article  CAS  PubMed  Google Scholar 

  9. Cui, Y. The role of lymphatic vessels in the heart. Pathophysiology 17, 307–314 (2010).

    Article  PubMed  Google Scholar 

  10. Ishikawa, Y. et al. Lymphangiogenesis in myocardial remodelling after infarction. Histopathology 51, 345–353 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kholová, I. et al. Lymphatic vasculature is increased in heart valves, ischaemic and inflamed hearts and in cholesterol-rich and calcified atherosclerotic lesions. Eur. J. Clin. Invest. 41, 487–497 (2011).

    Article  PubMed  Google Scholar 

  12. Klotz, L. et al. Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature 522, 62–67 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Henri, O. et al. Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction. Circulation 133, 1484–1497 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Aspelund, A., Robciuc, M. R., Karaman, S., Makinen, T. & Alitalo, K. Lymphatic system in cardiovascular medicine. Circ. Res. 118, 515–530 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Dashkevich, A., Hagl, C., Beyersdorf, F., Nykänen, A. I. & Lemström, K. B. VEGF pathways in the lymphatics of healthy and diseased heart. Microcirculation 23, 5–14 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Randolph, G. J., Ivanov, S., Zinselmeyer, B. H. & Scallan, J. P. The lymphatic system: integral roles in immunity. Annu. Rev. Immunol. 35, 31–52 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Vaahtomeri, K., Karaman, S., Mäkinen, T. & Alitalo, K. Lymphangiogenesis guidance by paracrine and pericellular factors. Genes Dev. 31, 1615–1634 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Scallan, J. P., Zawieja, S. D., Castorena-Gonzalez, J. A. & Davis, M. J. Lymphatic pumping: mechanics, mechanisms and malfunction: lymphatic pumping mechanisms. J. Physiol. 594, 5749–5768 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ma, Q., Ineichen, B. V., Detmar, M. & Proulx, S. T. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat. Commun. 8, 1434 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Antila, S. et al. Development and plasticity of meningeal lymphatic vessels. J. Exp. Med. 214, 3645–3667 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Louveau, A. et al. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J. Clin. Invest. 127, 3210–3219 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Levick, J. R. & Michel, C. C. Microvascular fluid exchange and the revised Starling principle. Cardiovasc. Res. 87, 198–210 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Hansen, K. C., D’Alessandro, A., Clement, C. C. & Santambrogio, L. Lymph formation, composition and circulation: a proteomics perspective. Int. Immunol. 27, 219–227 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Szabó, G. Enzymes in tissue fluid and peripheral lymph. Lymphology 11, 147–155 (1978).

    PubMed  Google Scholar 

  25. Dixon, J. B. Lymphatic lipid transport: sewer or subway? Trends Endocrinol. Metab. 21, 480–487 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huang, L.-H., Elvington, A. & Randolph, G. J. The role of the lymphatic system in cholesterol transport. Front. Pharmacol. 6, 182 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. Adair, T. H., Moffatt, D. S., Paulsen, A. W. & Guyton, A. C. Quantitation of changes in lymph protein concentration during lymph node transit. Am. J. Physiol. 243, H351–H359 (1982).

    CAS  PubMed  Google Scholar 

  28. Knox, P. & Pflug, J. J. The effect of the canine popliteal node on the composition of lymph. J. Physiol. 345, 1–14 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dieterich, L. C., Seidel, C. D. & Detmar, M. Lymphatic vessels: new targets for the treatment of inflammatory diseases. Angiogenesis 17, 359–371 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Tammela, T. & Alitalo, K. Lymphangiogenesis: molecular mechanisms and future promise. Cell 140, 460–476 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Yu, P., Tung, J. K. & Simons, M. Lymphatic fate specification: an ERK-controlled transcriptional program. Microvasc. Res. 96, 10–15 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Risebro, C. A. et al. Prox1 maintains muscle structure and growth in the developing heart. Development 136, 495–505 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Petchey, L. K. et al. Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy. Proc. Natl Acad. Sci. USA 111, 9515–9520 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kivelä, R. et al. The transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre-type regulation. Nat. Commun. 7, 13124 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Bernier-Latmani, J. et al. DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport. J. Clin. Invest. 125, 4572–4586 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Nurmi, H. et al. VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption. EMBO Mol. Med. 7, 1418–1425 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Norrmén, C., Tammela, T., Petrova, T. V. & Alitalo, K. Biological basis of therapeutic lymphangiogenesis. Circulation 123, 1335–1351 (2011).

    Article  PubMed  Google Scholar 

  38. Sappey, M. P. C. Anatomie, physiologie, pathologie des vaisseaux lymphatiques considérés chez l’homme et les vertébrés (Adrien Delahaye, Paris, 1874).

    Google Scholar 

  39. Ratajska, A. et al. Comparative and developmental anatomy of cardiac lymphatics. ScientificWorldJournal 2014, 183170 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shimada, T., Zhang, L., Abe, K., Yamabe, M. & Miyamoto, T. Developmental morphology of blood and lymphatic capillary networks in mammalian hearts, with special reference to three-dimensional architecture. Ital. J. Anat. Embryol. 106, 203–211 (2001).

    CAS  PubMed  Google Scholar 

  41. Juszyński, M., Ciszek, B., Stachurska, E., Jabłońska, A. & Ratajska, A. Development of lymphatic vessels in mouse embryonic and early postnatal hearts. Dev. Dyn. 237, 2973–2986 (2008).

    Article  PubMed  Google Scholar 

  42. Karunamuni, G. et al. Expression of lymphatic markers during avian and mouse cardiogenesis. Anat. Rec. 293, 259–270 (2010).

    Article  CAS  Google Scholar 

  43. Sabine, A., Saygili Demir, C. & Petrova, T. V. Endothelial cell responses to biomechanical forces in lymphatic vessels. Antioxid. Redox Signal. 25, 451–465 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Ulvmar, M. H., Martinez-Corral, I., Stanczuk, L. & Mäkinen, T. Pdgfrb-Cre targets lymphatic endothelial cells of both venous and non-venous origins. Genes 54, 350–358 (2016).

    Article  CAS  Google Scholar 

  45. Ulvmar, M. H. & Mäkinen, T. Heterogeneity in the lymphatic vascular system and its origin. Cardiovasc. Res. 111, 310–321 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mäkinen, T. et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat. Med. 7, 199–205 (2001).

    Article  PubMed  Google Scholar 

  47. Shimada, T., Noguchi, T., Takita, K., Kitamura, H. & Nakamura, M. Morphology of lymphatics of the mammalian heart with special reference to the architecture and distribution of the subepicardial lymphatic system. Acta Anat. 136, 16–20 (1989).

    Article  CAS  PubMed  Google Scholar 

  48. Miller, A. J., Pick, R. & Katz, L. N. Lymphatics of the mitral valve of the dog. Demonstration and discussion of the possible significance. Circ. Res. 9, 1005–1009 (1961).

    Article  CAS  PubMed  Google Scholar 

  49. Sacchi, G., Weber, E., Aglianò, M., Cavina, N. & Comparini, L. Lymphatic vessels of the human heart: precollectors and collecting vessels. A morpho-structural study. J. Submicrosc. Cytol. Pathol. 31, 515–525 (1999).

    CAS  PubMed  Google Scholar 

  50. Johnson, R. A. & Blake, T. M. Lymphatics of the heart. Circulation 33, 137–142 (1966).

    Article  CAS  PubMed  Google Scholar 

  51. Laine, G. A. & Allen, S. J. Left ventricular myocardial edema. Lymph flow, interstitial fibrosis, and cardiac function. Circ. Res. 68, 1713–1721 (1991).

    Article  CAS  PubMed  Google Scholar 

  52. Mehlhorn, U. et al. Impact of cardiopulmonary bypass and cardioplegic arrest on myocardial lymphatic function. Am. J. Physiol. 268, H178–H183 (1995).

    CAS  PubMed  Google Scholar 

  53. Schertel, E. R. et al. Mechanical workload-myocardial water content relationship in isolated rat hearts. Am. J. Physiol. 273, H271–H278 (1997).

    CAS  PubMed  Google Scholar 

  54. Geissler, H. J., Mehlhorn, U., Laine, G. A. & Allen, S. The effect of cardiopulmonary lymphatic obstruction on heart and lung function. Thorac. Cardiovasc. Surg. 49, 384 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Julien, P., Downar, E. & Angel, A. Lipoprotein composition and transport in the pig and dog cardiac lymphatic system. Circ. Res. 49, 248–254 (1981).

    Article  CAS  PubMed  Google Scholar 

  56. Barrett, T., Choyke, P. L. & Kobayashi, H. Imaging of the lymphatic system: new horizons. Contrast Media Mol. Imaging 1, 230–245 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Lucarelli, R. T. et al. New approaches to lymphatic imaging. Lymphat. Res. Biol. 7, 205–214 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Martel, C. et al. Photoacoustic lymphatic imaging with high spatial-temporal resolution. J. Biomed. Opt. 19, 116009 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Perin, E. C. et al. Imaging long-term fate of intramyocardially implanted mesenchymal stem cells in a porcine myocardial infarction model. PLOS ONE 6, e22949 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Santos, A. C. et al. Cardiac lymphatic dynamics after ischemia and reperfusion — experimental model. Nucl. Med. Biol. 25, 685–688 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Zawieja, S. D., Castorena-Gonzalez, J. A., Dixon, B. & Davis, M. J. Experimental models used to assess lymphatic contractile function. Lymphat. Res. Biol. 15, 331–342 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Leeds, S. E. & Uhley, H. N. Measurement of lymph flow of the heart. Lymphology 4, 31–34 (1971).

    CAS  PubMed  Google Scholar 

  63. Miller, A. J., Pick, R. & Johnson, P. J. The rates of formation of cardiac lymph and pericardial fluid after the production of myocardial venous congestion in dogs. Lymphology 5, 156–160 (1972).

    CAS  PubMed  Google Scholar 

  64. Mehlhorn, U., Geissler, H. J., Laine, G. A. & Allen, S. J. Myocardial fluid balance. Eur. J. Cardiothorac. Surg. 20, 1220–1230 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Laine, G. A. & Granger, H. J. Microvascular, interstitial, and lymphatic interactions in normal heart. Am. J. Physiol. 249, H834–H842 (1985).

    CAS  PubMed  Google Scholar 

  66. Feola, M. & Lefer, A. M. Alterations in cardiac lymph dynamics in acute myocardial ischemia in dogs. J. Surg. Res. 23, 299–305 (1977).

    Article  CAS  PubMed  Google Scholar 

  67. Nakamura, K. & Rockson, S. G. The role of the lymphatic circulation in the natural history and expression of cardiovascular disease. Int. J. Cardiol. 129, 309–317 (2008).

    Article  PubMed  Google Scholar 

  68. Kim, H., Kataru, R. P. & Koh, G. Y. Regulation and implications of inflammatory lymphangiogenesis. Trends Immunol. 33, 350–356 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Vieira, J. M. et al. The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. J. Clin. Invest. 128, 3402–3412 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Yeo, K. P. & Angeli, V. Bidirectional crosstalk between lymphatic endothelial cell and T Cell and its implications in tumor immunity. Front. Immunol. 8, 83 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Frangogiannis, N. G. The inflammatory response in myocardial injury, repair, and remodelling. Nat. Rev. Cardiol. 11, 255–265 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hulsmans, M., Sam, F. & Nahrendorf, M. Monocyte and macrophage contributions to cardiac remodeling. J. Mol. Cell. Cardiol. 93, 149–155 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Meng, X. et al. Regulatory T cells in cardiovascular diseases. Nat. Rev. Cardiol. 13, 167–179 (2016).

    Article  CAS  PubMed  Google Scholar 

  74. Ruparelia, N., Chai, J. T., Fisher, E. A. & Choudhury, R. P. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat. Rev. Cardiol. 14, 133–144 (2017).

    Article  CAS  PubMed  Google Scholar 

  75. von Knobelsdorff-Brenkenhoff, F. & Schulz-Menger, J. Cardiovascular magnetic resonance imaging in ischemic heart disease. J. Magn. Reson. Imaging 36, 20–38 (2012).

    Article  Google Scholar 

  76. Croisille, P., Kim, H. W. & Kim, R. J. Controversies in cardiovascular MR imaging: T2-weighted imaging should not be used to delineate the area at risk in ischemic myocardial injury. Radiology 265, 12–22 (2012).

    Article  PubMed  Google Scholar 

  77. Mavrogeni, S. et al. T1 and T2 mapping in cardiology: ‘mapping the obscure object of desire’. Cardiology 138, 207–217 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Lota, A. S., Gatehouse, P. D. & Mohiaddin, R. H. T2 mapping and T2* imaging in heart failure. Heart Fail. Rev. 22, 431–440 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Verbrugge, F. H. et al. Global myocardial oedema in advanced decompensated heart failure. Eur. Heart J. Cardiovasc. Imaging 18, 787–794 (2017).

    Article  PubMed  Google Scholar 

  80. Mehlhorn, U., Davis, K. L., Laine, G. A., Geissler, H. J. & Allen, S. J. Myocardial fluid balance in acute hypertension. Microcirculation 3, 371–378 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. Nishii, T. et al. Cardiovascular magnetic resonance T2 mapping can detect myocardial edema in idiopathic dilated cardiomyopathy. Int. J. Cardiovasc. Imaging 30 (Suppl. 1), 65–72 (2014).

    Article  PubMed  Google Scholar 

  82. Baeßler, B. et al. Mapping tissue inhomogeneity in acute myocarditis: a novel analytical approach to quantitative myocardial edema imaging by T2-mapping. J. Cardiovasc. Magn. Reson. 17, 115 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Nilsson, J. C. Sustained postinfarction myocardial oedema in humans visualised by magnetic resonance imaging. Heart 85, 639–642 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Carberry, J. et al. Persistence of infarct zone T2 hyperintensity at 6 months after acute ST-segment-elevation myocardial infarction: incidence, pathophysiology, and prognostic implications. Circ. Cardiovasc. Imaging 10, e006586 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Desai, K. V. et al. Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema. Am. J. Physiol. Heart Circ. Physiol. 294, H2428–H2434 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Dongaonkar, R. M., Stewart, R. H., Geissler, H. J. & Laine, G. A. Myocardial microvascular permeability, interstitial oedema, and compromised cardiac function. Cardiovasc. Res. 87, 331–339 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kline, I. K., Miller, A. J. & Katz, L. N. Cardiac lymph flow impairment and myocardial fibrosis. Effects of chronic obstruction in dogs. Arch. Pathol. 76, 424–433 (1963).

    CAS  PubMed  Google Scholar 

  88. Ludwig, L. L. et al. Impairment of left ventricular function by acute cardiac lymphatic obstruction. Cardiovasc. Res. 33, 164–171 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Kong, D., Kong, X. & Wang, L. Effect of cardiac lymph flow obstruction on cardiac collagen synthesis and interstitial fibrosis. Physiol. Res. 55, 253–258 (2006).

    CAS  PubMed  Google Scholar 

  90. Dashkevich, A., Bloch, W., Antonyan, A., Fries, J. U. W. & Geissler, H. J. Morphological and quantitative changes of the initial myocardial lymphatics in terminal heart failure. Lymphat. Res. Biol. 7, 21–27 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Niinimäki, E., Mennander, A. A., Paavonen, T. & Kholová, I. Lymphangiogenesis is increased in heart valve endocarditis. Int. J. Cardiol. 219, 317–321 (2016).

    Article  PubMed  Google Scholar 

  92. Syväranta, S., Helske, S., Lappalainen, J., Kupari, M. & Kovanen, P. T. Lymphangiogenesis in aortic valve stenosis — novel regulatory roles for valvular myofibroblasts and mast cells. Atherosclerosis 221, 366–374 (2012).

    Article  PubMed  CAS  Google Scholar 

  93. Geissler, H. J. et al. First year changes of myocardial lymphatic endothelial markers in heart transplant recipients. Eur. J. Cardiothorac. Surg. 29, 767–771 (2006).

    Article  PubMed  Google Scholar 

  94. Wong, B. W., Wong, D., Luo, H. & McManus, B. M. Vascular endothelial growth factor-D is overexpressed in human cardiac allograft vasculopathy and diabetic atherosclerosis and induces endothelial permeability to low-density lipoproteins in vitro. J. Heart Lung Transplant. 30, 955–962 (2011).

    PubMed  Google Scholar 

  95. Park, J.-H. et al. Endothelial progenitor cell transplantation decreases lymphangiogenesis and adverse myocardial remodeling in a mouse model of acute myocardial infarction. Exp. Mol. Med. 43, 479–485 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cimini, M., Cannatá, A., Pasquinelli, G., Rota, M. & Goichberg, P. Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium. PLOS ONE 12, e0173927 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Tatin, F. et al. Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction. JCI Insight 2, 93887 (2017).

    Article  PubMed  Google Scholar 

  98. Nykänen, A. I. et al. 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, 1413–1422 (2010).

    Article  PubMed  CAS  Google Scholar 

  99. Dashkevich, A. et al. Ischemia-reperfusion injury enhances lymphatic endothelial VEGFR3 and rejection in cardiac allografts. Am. J. Transplant. 16, 1160–1172 (2016).

    Article  CAS  PubMed  Google Scholar 

  100. Greiwe, L., Vinck, M. & Suhr, F. The muscle contraction mode determines lymphangiogenesis differentially in rat skeletal and cardiac muscles by modifying local lymphatic extracellular matrix microenvironments. Acta Physiol. 217, 61–79 (2016).

    Article  CAS  Google Scholar 

  101. Khan, S., Khan, S., Baboota, S. & Ali, J. Immunosuppressive drug therapy — biopharmaceutical challenges and remedies. Expert Opin. Drug Deliv. 12, 1333–1349 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Ebata, R. et al. Increased production of vascular endothelial growth factor-d and lymphangiogenesis in acute Kawasaki disease. Circ. J. 75, 1455–1462 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Lupinski, R. W. Aortic fat pad and atrial fibrillation: cardiac lymphatics revisited. ANZ J. Surg. 79, 70–74 (2009).

    Article  PubMed  Google Scholar 

  104. Miller, A. J., DeBoer, A. & Palmer, A. The role of the lymphatic system in coronary atherosclerosis. Med. Hypotheses 37, 31–36 (1992).

    Article  CAS  PubMed  Google Scholar 

  105. Sacchi, G., Weber, E. & Comparini, L. Histological framework of lymphatic vasa vasorum of major arteries: an experimental study. Lymphology 23, 135–139 (1990).

    CAS  PubMed  Google Scholar 

  106. Sano, M. et al. Topologic distributions of vasa vasorum and lymphatic vasa vasorum in the aortic adventitia — implications for the prevalence of aortic diseases. Atherosclerosis 247, 127–134 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. Hjelms, E., Nordestgaard, B. G., Stender, S. & Kjeldsen, K. A surgical model to study in vivo efflux of cholesterol from porcine aorta. Evidence for cholesteryl ester transfer through the aortic wall. Atherosclerosis 77, 239–249 (1989).

    Article  CAS  PubMed  Google Scholar 

  108. Lim, H. Y. et al. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab. 17, 671–684 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Lemole, G. M. The role of lymphstasis in atherogenesis. Ann. Thorac. Surg. 31, 290–293 (1981).

    Article  CAS  PubMed  Google Scholar 

  110. Nakano, T. et al. Angiogenesis and lymphangiogenesis and expression of lymphangiogenic factors in the atherosclerotic intima of human coronary arteries. Hum. Pathol. 36, 330–340 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Drozdz, K. et al. Adventitial lymphatics and atherosclerosis. Lymphology 45, 26–33 (2012).

    CAS  PubMed  Google Scholar 

  112. Grzegorek, I. et al. Arterial wall lymphangiogenesis is increased in the human iliac atherosclerotic arteries: involvement of CCR7 receptor. Lymphat. Res. Biol. 12, 222–231 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Rademakers, T. et al. Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis. Sci. Rep. 7, 45263 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Rutanen, J. et al. Vascular endothelial growth factor-D expression in human atherosclerotic lesions. Cardiovasc. Res. 59, 971–979 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Taher, M. et al. Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2. FASEB J. 30, 2490–2499 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Martel, C. et al. Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J. Clin. Invest. 123, 1571–1579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Vuorio, T. et al. Lymphatic vessel insufficiency in hypercholesterolemic mice alters lipoprotein levels and promotes atherogenesis. Arterioscler. Thromb. Vasc. Biol. 34, 1162–1170 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Simons, M. & Ware, J. A. Therapeutic angiogenesis in cardiovascular disease. Nat. Rev. Drug Discov. 2, 863–872 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Ennett, A. B. & Mooney, D. J. Tissue engineering strategies for in vivo neovascularisation. Expert Opin. Biol. Ther. 2, 805–818 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Mao, A. S. & Mooney, D. J. Regenerative medicine: current therapies and future directions. Proc. Natl Acad. Sci. USA 112, 14452–14459 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ylä-Herttuala, S. & Baker, A. H. Cardiovascular gene therapy: past, present, and future. Mol. Ther. 25, 1095–1106 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Jeltsch, M. et al. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation 129, 1962–1971 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. Bui, H. M. et al. Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD. J. Clin. Invest. 126, 2167–2180 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Jha, S. K. et al. Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1. Sci. Rep. 7, 4916 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Joukov, V. et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 16, 3898–3911 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zhou, Q. et al. Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice. Arthritis Rheum. 63, 2318–2328 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Tammela, T. et al. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat. Med. 13, 1458–1466 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Heinolainen, K. et al. VEGFR3 modulates vascular permeability by controlling VEGF/VEGFR2 signaling. Circ. Res. 120, 1414–1425 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Saaristo, A. et al. Lymphangiogenic gene therapy with minimal blood vascular side effects. J. Exp. Med. 196, 719–730 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Toivanen, P. I. et al. Novel vascular endothelial growth factor D variants with increased biological activity. J. Biol. Chem. 284, 16037–16048 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Anisimov, A. et al. Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle. Circ. Res. 104, 1302–1312 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Goichberg, P. Therapeutic lymphangiogenesis after myocardial infarction: vascular endothelial growth factor-C paves the way. J. Thorac. Dis. 8, 1904–1907 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Losordo, D. W. et al. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 105, 2012–2018 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Witzenbichler, B. et al. Vascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia. Am. J. Pathol. 153, 381–394 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Carmeliet, P. & Conway, E. M. Growing better blood vessels. Nat. Biotechnol. 19, 1019–1020 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Simons, M. & Eichmann, A. Molecular controls of arterial morphogenesis. Circ. Res. 116, 1712–1724 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Cao, R. et al. Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proc. Natl Acad. Sci. USA 109, 15894–15899 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Hartikainen, J. et al. Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur. Heart J. 38, 2547–2555 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Bianchi, R. et al. Postnatal deletion of podoplanin in lymphatic endothelium results in blood filling of the lymphatic system and impairs dendritic cell migration to lymph nodes. Arterioscler. Thromb. Vasc. Biol. 37, 108–117 (2017).

    Article  CAS  PubMed  Google Scholar 

  140. Stein, J. V. & Nombela-Arrieta, C. Chemokine control of lymphocyte trafficking: a general overview. Immunology 116, 1–12 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ohl, L. et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Kiermaier, E. et al. Polysialylation controls dendritic cell trafficking by regulating chemokine recognition. Science 351, 186–190 (2016).

    Article  CAS  PubMed  Google Scholar 

  143. Aebischer, D., Iolyeva, M. & Halin, C. The inflammatory response of lymphatic endothelium. Angiogenesis 17, 383–393 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. Haemmerle, M. et al. Enhanced lymph vessel density, remodeling, and inflammation are reflected by gene expression signatures in dermal lymphatic endothelial cells in type 2 diabetes. Diabetes 62, 2509–2529 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Girard, J.-P., Moussion, C. & Förster, R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat. Rev. Immunol. 12, 762–773 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. Teijeira, A. et al. T cell migration from inflamed skin to draining lymph nodes requires intralymphatic crawling supported by ICAM-1/LFA-1 interactions. Cell Rep. 18, 857–865 (2017).

    Article  CAS  PubMed  Google Scholar 

  147. Chakraborty, S., Zawieja, S., Wang, W., Zawieja, D. C. & Muthuchamy, M. Lymphatic system: a vital link between metabolic syndrome and inflammation: roles of lymphatics in metabolic syndrome. Ann. NY Acad. Sci. 1207, E94–E102 (2010).

    Article  PubMed  Google Scholar 

  148. Palframan, R. T. et al. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J. Exp. Med. 194, 1361–1373 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kataru, R. P. et al. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113, 5650–5659 (2009).

    Article  CAS  PubMed  Google Scholar 

  150. D’Alessio, S. et al. VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J. Clin. Invest. 124, 3863–3878 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Tewalt, E. F., Cohen, J. N., Rouhani, S. J. & Engelhard, V. H. Lymphatic endothelial cells — key players in regulation of tolerance and immunity. Front. Immunol. 3, 305 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Christiansen, A. J. et al. Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation. Oncotarget 7, 39421–39435 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Trevaskis, N. L., Kaminskas, L. M. & Porter, C. J. H. From sewer to saviour — targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. 14, 781–803 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. Tamburini, B. A., Burchill, M. A. & Kedl, R. M. Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection. Nat. Commun. 5, 3989 (2014).

    Article  CAS  PubMed  Google Scholar 

  155. Dietrich, T. et al. Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J. Immunol. 184, 535–539 (2010).

    Article  CAS  PubMed  Google Scholar 

  156. Dieterich, L. C. et al. Tumor-associated lymphatic vessels upregulate PDL1 to inhibit T-cell activation. Front. Immunol. 8, 66 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Bouta, E. M. et al. Brief report: treatment of tumor necrosis factor-transgenic mice with anti-tumor necrosis factor restores lymphatic contractions, repairs lymphatic vessels, and may increase monocyte/macrophage egress. Arthritis Rheumatol. 69, 1187–1193 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Liao, S. et al. Impaired lymphatic contraction associated with immunosuppression. Proc. Natl Acad. Sci. USA 108, 18784–18789 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Jantsch, J., Binger, K. J., Müller, D. N. & Titze, J. Macrophages in homeostatic immune function. Front. Physiol. 5, 146 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Van der Borght, K. et al. Myocardial infarction primes autoreactive T cells through activation of dendritic cells. Cell Rep. 18, 3005–3017 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Angeli, V. et al. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24, 203–215 (2006).

    Article  CAS  PubMed  Google Scholar 

  162. Ghanta, S. et al. Regulation of inflammation and fibrosis by macrophages in lymphedema. Am. J. Physiol. Heart Circ. Physiol. 308, H1065–H1077 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Cao, Y. Opinion: emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis. Nat. Rev. Cancer 5, 735–743 (2005).

    Article  CAS  PubMed  Google Scholar 

  164. Kataru, R. P. et al. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34, 96–107 (2011).

    Article  CAS  PubMed  Google Scholar 

  165. Weichand, B. et al. S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. J. Exp. Med. 214, 2695–2713 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Baluk, P. et al. Transgenic overexpression of interleukin-1β induces persistent lymphangiogenesis but not angiogenesis in mouse airways. Am. J. Pathol. 182, 1434–1447 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ristimäki, A., Narko, K., Enholm, B., Joukov, V. & Alitalo, K. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J. Biol. Chem. 273, 8413–8418 (1998).

    Article  PubMed  Google Scholar 

  168. Ji, H. et al. TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling. Nat. Commun. 5, 4944 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. Loukas, M. et al. in The Cardiac Lymphatic System: An Overview (ed. Karunamuni, G.) 3–15 (Springer, New York, 2013).

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Acknowledgements

The authors thank A. Ratajska (Warsaw Medical University, Poland) for critical reading of the manuscript, and they acknowledge the work of colleagues and collaborators in providing the background research for this Review. Special thanks goes to D. Godefroy (INSERM UMR1239-DC2N Laboratory, Rouen, France) and D. Schapmann (PRIMACEN, Rouen, France) for expert assistance with cardiac light sheet and confocal microscopy, respectively. E.B. is supported by the European Research Area Network (ERA-NET) on Cardiovascular Diseases (ERA-CVD) (LYMIT-DIS project, a transnational research and development programme jointly funded by national funding organizations within the framework of the ERA-NET ERA-CVD), FHU REMOD-VHF (INSERM U1096 laboratory) and generalized institutional funds from the French INSERM and the Normandy Region together with the European Union: “Europe gets involved in Normandie” with European Regional Development Fund (ERDF): CPER/FEDER 2015 (DO-IT) and CPER/FEDER 2016 (PACT-CBS). K.A. is supported by the Academy of Finland (Centre of Excellence Program 2014–2019 (271845 and 307366)), the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement 743155), the Novo Nordisk Foundation, the Sigrid Juselius Foundation, the Helsinki Institute for Life Sciences (HiLife), and the Finnish Cancer Society.

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Nature Reviews Cardiology thanks M. Achen, D. Kerjaschki, M. L. Khan and the other, anonymous reviewer for their contribution to the peer review of this work.

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  1. Normandy University, UniRouen, INSERM (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU REMOD-VHF, Rouen, France

    Ebba Brakenhielm

  2. Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland

    Kari Alitalo

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Brakenhielm, E., Alitalo, K. Cardiac lymphatics in health and disease. Nat Rev Cardiol 16, 56–68 (2019). https://doi.org/10.1038/s41569-018-0087-8

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