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Open Access 04-11-2021 | Heart Transplantation

The role of lymphangiogenesis in cardiovascular diseases and heart transplantation

Author: Rui-Cheng Ji

Published in: Heart Failure Reviews | Issue 5/2022

Abstract

Cardiac lymphangiogenesis plays an important physiological role in the regulation of interstitial fluid homeostasis, inflammatory, and immune responses. Impaired or excessive cardiac lymphatic remodeling and insufficient lymph drainage have been implicated in several cardiovascular diseases including atherosclerosis and myocardial infarction (MI). Although the molecular mechanisms underlying the regulation of functional lymphatics are not fully understood, the interplay between lymphangiogenesis and immune regulation has recently been explored in relation to the initiation and development of these diseases. In this field, experimental therapeutic strategies targeting lymphangiogenesis have shown promise by reducing myocardial inflammation, edema and fibrosis, and improving cardiac function. On the other hand, however, whether lymphangiogenesis is beneficial or detrimental to cardiac transplant survival remains controversial. In the light of recent evidence, cardiac lymphangiogenesis, a thriving and challenging field has been summarized and discussed, which may improve our knowledge in the pathogenesis of cardiovascular diseases and transplant biology.

Ji RC, Kato S (2001) Histochemical analysis of lymphatic endothelial cells in lymphostasis. Microsc Res Tech 55:70–80. https://doi.org/10.1002/jemt.1158CrossRefPubMed

Guo R, Zhou Q, Proulx ST, Wood R, Ji RC, Ritchlin CT, Pytowski B, Zhu Z, Wang YJ, Schwarz EM, Xing L (2009) Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum 60:2666–2676. https://doi.org/10.1002/art.24764CrossRefPubMedPubMedCentral

Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, Antsiferova M, Werner S, Alitalo K, Detmar M (2011) An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117:4667–4678. https://doi.org/10.1182/blood-2010-10-316356CrossRefPubMedPubMedCentral

Ji RC, Eshita Y, Kobayashi T, Hidano S, Kamiyama N, Onishi Y (2018) Role of simvastatin in tumor lymphangiogenesis and lymph node metastasis. Clin Exp Metastasis 35:785–796. https://doi.org/10.1007/s10585-018-9940-8CrossRefPubMed

Jackson DG (2019) Leucocyte Trafficking via the Lymphatic Vasculature- Mechanisms and Consequences. Front Immunol 10:471. https://doi.org/10.3389/fimmu.2019.00471

Kim JD, Kang Y, Kim J, Papangeli I, Kang H, Wu J, Park H, Nadelmann E, Rockson SG, Chun HJ, Jin SW (2014) Essential role of Apelin signaling during lymphatic development in zebrafish. Arterioscler Thromb Vasc Biol 34:338–345. https://doi.org/10.1161/ATVBAHA.113.302785CrossRefPubMed

Klotz L, Norman S, Vieira JM, Masters M, Rohling M, Dubé KN, Bollini S, Matsuzaki F, Carr CA, Riley PR (2015) Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature 522:62–67. https://doi.org/10.1038/nature14483CrossRefPubMedPubMedCentral

Harrison MR, Feng X, Mo G, Aguayo A, Villafuerte J, Yoshida T, Pearson CA, Schulte-Merker S, Lien CL (2019) Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration. Elife 8

Aurora AB, Porrello ER, Tan W, Mahmoud AI, Hill JA, Bassel-Duby R, Sadek HA, Olson EN (2014) Macrophages are required for neonatal heart regeneration. J Clin Invest 124:1382–1392. https://doi.org/10.1172/JCI72181CrossRefPubMedPubMedCentral

10.

Merz SF, Korste S, Bornemann L, Michel L, Stock P, Squire A, Soun C, Engel DR, Detzer J, Lörchner H, Hermann DM, Kamler M, Klode J, Hendgen-Cotta UB, Rassaf T, Gunzer M, Totzeck M (2019) Contemporaneous 3D characterization of acute and chronic myocardial I/R injury and response. Nat Commun 10:2312. https://doi.org/10.1038/s41467-019-10338-2

11.

Klaourakis K, Vieira JM, Riley PR (2021) The evolving cardiac lymphatic vasculature in development, repair and regeneration. Nat Rev Cardiol 18:368–379. https://doi.org/10.1038/s41569-020-00489-x

12.

Liu X, De la Cruz E, Gu X, Balint L, Oxendine-Burns M, Terrones T, Ma W, Kuo HH, Lantz C, Bansal T, Thorp E, Burridge P, Jakus Z, Herz J, Cleaver O, Torres M, Oliver G (2020) Lymphoangiocrine signals promote cardiac growth and repair. Nature 588:705–711. https://doi.org/10.1038/s41586-020-2998-x

13.

Houssari M, Dumesnil A, Tardif V, Kivelä R, Pizzinat N, Boukhalfa I, Godefroy D, Schapman D, Hemanthakumar KA, Bizou M, Henry JP, Renet S, Riou G, Rondeaux J, Anouar Y, Adriouch S, Fraineau S, Alitalo K, Richard V, Mulder P, Brakenhielm E (2020) Lymphatic and immune cell cross-talk regulates cardiac recovery after experimental myocardial infarction. Arterioscler Thromb Vasc Biol 40:1722–1737. https://doi.org/10.1161/ATVBAHA.120.314370

14.

Iwamiya T, Segard BD, Matsuoka Y, Imamura T (2020) Human cardiac fibroblasts expressing VCAM1 improve heart function in postinfarct heart failure rat models by stimulating lymphangiogenesis. PLoS One 15:e0237810. https://doi.org/10.1371/journal.pone.0237810

15.

Bhattacharjee S, Lee Y, Zhu B, Wu H, Chen Y, Chen H (2021) Epsins in vascular development, function and disease. Cell Mol Life Sci 78:833–842. https://doi.org/10.1007/s00018-020-03642-4

16.

Oliver G, Kipnis J, Randolph GJ, Harvey NL (2020) The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease. Cell 182:270–296. https://doi.org/10.1016/j.cell.2020.06.039

17.

Brakenhielm E, González A, Díez J (2020) Role of cardiac lymphatics in myocardial edema and fibrosis: JACC review topic of the week. J Am Coll Cardiol 76:735–744. https://doi.org/10.1016/j.jacc.2020.05.076

18.

Lakkis FG, Arakelov A, Konieczny BT, Inoue Y (2000) Immunologic 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med 6:686–688. https://doi.org/10.1038/76267

19.

Dashkevich A, Raissadati A, Syrjälä SO, Zarkada G, Keränen MA, Tuuminen R, Krebs R, Anisimov A, Jeltsch M, Leppänen VM, Alitalo K, Nykänen AI, Lemström KB (2016) Ischemia-reperfusion injury enhances lymphatic endothelial VEGFR3 and rejection in cardiac allografts. Am J Transplant 16:1160–1172. https://doi.org/10.1111/ajt.13564

20.

Nykänen AI, Sandelin H, Krebs R, Keränen MA, Tuuminen R, Kärpänen T, Wu Y, Pytowski B, Koskinen PK, Ylä-Herttuala S, Alitalo K, Lemström KB (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 121:1413–1422. https://doi.org/10.1161/CIRCULATIONAHA.109.910703

21.

Zhu J, Inomata T, Fujimoto K, Uchida K, Fujio K, Nagino K, Miura M, Negishi N, Okumura Y, Akasaki Y, Hirosawa K, Kuwahara M, Eguchi A, Shokirova H, Yanagawa A, Midorikawa-Inomata A, Murakami A (2021) Ex vivo-induced bone marrow-derived myeloid suppressor cells prevent corneal allograft rejection in mice. Invest Ophthalmol Vis Sci 62:3. https://doi.org/10.1167/iovs.62.7.3

22.

Ratajska A, Gula G, Flaht-Zabost A, Czarnowska E, Ciszek B, Jankowska-Steifer E, Niderla-Bielinska J, Radomska-Lesniewska D (2014) Comparative and developmental anatomy of cardiac lymphatics. ScientificWorldJournal 2014:183170. https://doi.org/10.1155/2014/183170

23.

Tatin F, Renaud-Gabardos E, Godet AC, Hantelys F, Pujol F, Morfoisse F, Calise D, Viars F, Valet P, Masri B, Prats AC, Garmy-Susini B (2017) Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction. JCI Insight 2:e93887. https://doi.org/10.1172/jci.insight.93887

24.

Vuorio T, Ylä-Herttuala E, Laakkonen JP, Laidinen S, Liimatainen T, Ylä-Herttuala S (2018) Downregulation of VEGFR3 signaling alters cardiac lymphatic vessel organization and leads to a higher mortality after acute myocardial infarction. Sci Rep 8:16709. https://doi.org/10.1038/s41598-018-34770-4

25.

Henri O, Pouehe C, Houssari M, Galas L, Nicol L, Edwards-Lévy F, Henry JP, Dumesnil A, Boukhalfa I, Banquet S, Schapman D, Thuillez C, Richard V, Mulder P, Brakenhielm E (2016) Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction. Circulation 133:1484–1497. https://doi.org/10.1161/CIRCULATIONAHA.115.020143

26.

Ji RC (2018) Recent advances and new insights into muscular lymphangiogenesis in health and disease. Life Sci 211:261–269. https://doi.org/10.1016/j.lfs.2018.09.043

27.

Flaht-Zabost A, Gula G, Ciszek B, Czarnowska E, Jankowska-Steifer E, Madej M, Niderla-Bielińska J, Radomska-Leśniewska D, Ratajska A (2014) Cardiac mouse lymphatics: developmental and anatomical update. Anat Rec (Hoboken) 297:1115–1130. https://doi.org/10.1002/ar.22912

28.

Lioux G, Liu X, Temiño S, Oxendine M, Ayala E, Ortega S, Kelly RG, Oliver G, Torres M (2020) A second heart field-derived vasculogenic niche contributes to cardiac lymphatics. Dev Cell 52:350–363.e6. https://doi.org/10.1016/j.devcel.2019.12.006

29.

Cahill TJ, Sun X, Ravaud C, Villa Del Campo C, Klaourakis K, Lupu IE, Lord AM, Browne C, Jacobsen SEW, Greaves DR, Jackson DG, Cowley SA, James W, Choudhury RP, Vieira JM, Riley PR (2021) Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart. Development 148:dev194563. https://doi.org/10.1242/dev.194563

30.

Kholová I, Dragneva G, Cermáková P, Laidinen S, Kaskenpää N, Hazes T, Cermáková E, Steiner I, Ylä-Herttuala S (2011) 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. https://doi.org/10.1111/j.1365-2362.2010.02431.x

31.

Emini Veseli B, Perrotta P, De Meyer GRA, Roth L, Van der Donckt C, Martinet W, De Meyer GRY (2017) Animal models of atherosclerosis. Eur J Pharmacol 816:3–813. https://doi.org/10.1016/j.ejphar.2017.05.010

32.

Urner S, Planas-Paz L, Hilger LS, Henning C, Branopolski A, Kelly-Goss M, Stanczuk L, Pitter B, Montanez E, Peirce SM, Mäkinen T, Lammert E (2019) Identification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth. EMBO J 38:e99322. https://doi.org/10.15252/embj.201899322

33.

Cimini M, Cannatá A, Pasquinelli G, Rota M, Goichberg P (2017) 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. https://doi.org/10.1371/journal.pone.0173927

34.

Galkina E, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis (*). Annu Rev Immunol 27:165–197. https://doi.org/10.1146/annurev.immunol.021908.132620

35.

Rafieian-Kopaei M, Setorki M, Doudi M, Baradaran A, Nasri H (2014) Atherosclerosis: process, indicators, risk factors and new hopes. Int J Prev Med 5:927–946PubMedPubMedCentral

36.

Randolph GJ, Miller NE (2014) Lymphatic transport of high-density lipoproteins and chylomicrons. J Clin Invest 124:929–935. https://doi.org/10.1172/JCI71610

37.

Ouimet M, Barrett TJ, Fisher EA (2019) HDL and reverse cholesterol transport. Circ Res 124:1505–1518. https://doi.org/10.1161/CIRCRESAHA.119.312617

38.

Huang LH, Elvington A, Randolph GJ (2015) The role of the lymphatic system in cholesterol transport. Front Pharmacol 6:182. https://doi.org/10.3389/fphar.2015.00182

39.

Drozdz K, Janczak D, Dziegiel P, Podhorska M, Patrzałek D, Ziółkowski P, Andrzejak R, Szuba A (2008) Adventitial lymphatics of internal carotid artery in healthy and atherosclerotic vessels. Folia Histochem Cytobiol 46:433–436. https://doi.org/10.2478/v10042-008-0083-7

40.

Rademakers T, van der Vorst EP, Daissormont IT, Otten JJ, Theodorou K, Theelen TL, Gijbels M, Anisimov A, Nurmi H, Lindeman JH, Schober A, Heeneman S, Alitalo K, Biessen EA (2017) Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis. Sci Rep 7:45263. https://doi.org/10.1038/srep45263

41.

Lim HY, Thiam CH, Yeo KP, Bisoendial R, Hii CS, McGrath KC, Tan KW, Heather A, Alexander JS, Angeli V (2013) Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab 17:671–684. https://doi.org/10.1016/j.cmet.2013.04.002

42.

Milasan A, Smaani A, Martel C (2019) Early rescue of lymphatic function limits atherosclerosis progression in Ldlr-/- mice. Atherosclerosis 283:106–119. https://doi.org/10.1016/j.atherosclerosis.2019.01.031

43.

Martel C, Li W, Fulp B, Platt AM, Gautier EL, Westerterp M, Bittman R, Tall AR, Chen SH, Thomas MJ, Kreisel D, Swartz MA, Sorci-Thomas MG, Randolph GJ (2013) Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J Clin Invest 123:1571–1579. https://doi.org/10.1172/JCI63685

44.

Gracia G, Cao E, Johnston APR, Porter CJH, Trevaskis NL (2020) Organ-specific lymphatics play distinct roles in regulating HDL trafficking and composition. Am J Physiol Gastrointest Liver Physiol 318:G725-G735. https://doi.org/10.1152/ajpgi.00340.2019

45.

Out R, Hoekstra M, Habets K, Meurs I, de Waard V, Hildebrand RB, Wang Y, Chimini G, Kuiper J, Van Berkel TJ, Van Eck M (2008) Combined deletion of macrophage ABCA1 and ABCG1 leads to massive lipid accumulation in tissue macrophages and distinct atherosclerosis at relatively low plasma cholesterol levels. Arterioscler Thromb Vasc Biol 28:258–264. https://doi.org/10.1161/ATVBAHA.107.156935

46.

Trevaskis NL, Kaminskas LM, Porter CJ (2015) From sewer to saviour – targeting the lymphatic system to promote drug exposure and activity. Nat Rev Drug Discov 14:781–803. https://doi.org/10.1038/nrd4608

47.

Tessier N, Moawad F, Amri N, Brambilla D, Martel C (2021) Focus on the lymphatic route to optimize drug delivery in cardiovascular medicine. Pharmaceutics 13:1200. https://doi.org/10.3390/pharmaceutics13081200

48.

Weber C, Zernecke A, Libby P (2008) The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 8:802–815. https://doi.org/10.1038/nri2415

49.

Xing L, Ji RC (2008) Lymphangiogenesis, myeloid cells and inflammation. Expert Rev Clin Immunol 4:599–613. https://doi.org/10.1586/1744666X.4.5.599

50.

Hansson GK, Hermansson A (2011) The immune system in atherosclerosis. Nat Immunol 12:204–212. https://doi.org/10.1038/ni.2001

51.

Kataru RP, Kim H, Jang C, Choi DK, Koh BI, Kim M, Gollamudi S, Kim YK, Lee SH, Koh GY (2011) T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34:96–107. https://doi.org/10.1016/j.immuni.2010.12.016

52.

Ji RC, Eshita Y (2014) Rapamycin inhibition of CFA-induced lymphangiogenesis in PLN is independent of mast cells. Mol Biol Rep 41:2217–2228. https://doi.org/10.1007/s11033-014-3073-1

53.

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

54.

Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nuñez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361. https://doi.org/10.1038/nature08938

55.

Hermansson A, Ketelhuth DF, Strodthoff D, Wurm M, Hansson EM, Nicoletti A, Paulsson-Berne G, Hansson GK (2010) Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med 207:1081–1093. https://doi.org/10.1084/jem.20092243

56.

Aspelund A, Robciuc MR, Karaman S, Makinen T, Alitalo K (2016) Lymphatic system in cardiovascular medicine. Circ Res 118:515–530. https://doi.org/10.1161/CIRCRESAHA.115.306544

57.

Singla B, Lin HP, Ahn W, White J, Csányi G (2021) Oxidatively modified LDL suppresses lymphangiogenesis via CD36 signaling. Antioxidants (Basel) 10:331. https://doi.org/10.3390/antiox10020331

58.

Yeo KP, Lim HY, Thiam CH, Azhar SH, Tan C, Tang Y, See WQ, Koh XH, Zhao MH, Phua ML, Balachander A, Tan Y, Lim SY, Chew HS, Ng LG, Angeli V (2020) Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe. Sci Adv 6:eabc2697. https://doi.org/10.1126/sciadv.abc2697

59.

Singla B, Lin HP, Chen A, Ahn W, Ghoshal P, Cherian-Shaw M, White J, Stansfield BK, Csányi G (2021) Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis. Cardiovasc Res 117:1489–1509. https://doi.org/10.1093/cvr/cvaa244

60.

Agmon Y, Khandheria BK, Meissner I, Schwartz GL, Petterson TM, O'Fallon WM, Gentile F, Whisnant JP, Wiebers DO, Seward JB (2000) Independent association of high blood pressure and aortic atherosclerosis: a population-based study. Circulation 102:2087–2093. https://doi.org/10.1161/01.cir.102.17.2087

61.

Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Müller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J (2009) Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med 15:545–552. https://doi.org/10.1038/nm.1960

62.

Lopez Gelston CA, Balasubbramanian D, Abouelkheir GR, Lopez AH, Hudson KR, Johnson ER, Muthuchamy M, Mitchell BM, Rutkowski JM (2018) Enhancing renal lymphatic expansion prevents hypertension in mice. Circ Res 122:1094–1101. https://doi.org/10.1161/CIRCRESAHA.118.312765

63.

Balasubbramanian D, Gelston CAL, Lopez AH, Iskander G, Tate W, Holderness H, Rutkowski JM, Mitchell BM (2020) Augmenting renal lymphatic density prevents angiotensin II-induced hypertension in male and female mice. Am J Hypertens 33:61–69. https://doi.org/10.1093/ajh/hpz139

64.

Beaini S, Saliba Y, Hajal J, Smayra V, Bakhos JJ, Joubran N, Chelala D, Fares N (2019) VEGF-C attenuates renal damage in salt-sensitive hypertension. J Cell Physiol 234:9616–9630. https://doi.org/10.1002/jcp.27648

65.

Song L, Chen X, Swanson TA, LaViolette B, Pang J, Cunio T, Nagle MW, Asano S, Hales K, Shipstone A, Sobon H, Al-Harthy SD, Ahn Y, Kreuser S, Robertson A, Ritenour C, Voigt F, Boucher M, Sun F, Sessa WC, Roth Flach RJ (2020) Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension. Elife 9:e58376. https://doi.org/10.7554/eLife.58376

66.

Donnan MD, Kenig-Kozlovsky Y, Quaggin SE (2021) The lymphatics in kidney health and disease. Nat Rev Nephrol 17:655–675. https://doi.org/10.1038/s41581-021-00438-y

67.

Townsend EA, Miller VM, Prakash YS (2012) Sex differences and sex steroids in lung health and disease. Endocr Rev 33:1–47. https://doi.org/10.1210/er.2010-0031

68.

Boese AC, Kim SC, Yin KJ, Lee JP, Hamblin MH (2017) Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol 313:H524-H545. https://doi.org/10.1152/ajpheart.00217.2016

69.

Mahmoodzadeh S, Leber J, Zhang X, Jaisser F, Messaoudi S, Morano I, Furth PA, Dworatzek E, Regitz-Zagrosek V (2014) Cardiomyocyte-specific estrogen receptor alpha increases angiogenesis, lymphangiogenesis and reduces fibrosis in the female mouse heart post-myocardial infarction. J Cell Sci Ther 5:153. https://doi.org/10.4172/2157-7013.1000153

70.

Pollow DP, Uhrlaub J, Romero-Aleshire M, Sandberg K, Nikolich-Zugich J, Brooks HL, Hay M (2014) Sex differences in T-lymphocyte tissue infiltration and development of angiotensin II hypertension. Hypertension 64:384–390. https://doi.org/10.1161/HYPERTENSIONAHA.114.03581

71.

Trincot CE, Xu W, Zhang H, Kulikauskas MR, Caranasos TG, Jensen BC, Sabine A, Petrova TV, Caron KM (2019) Adrenomedullin induces cardiac lymphangiogenesis after myocardial infarction and regulates cardiac edema via connexin 43. Circ Res 124:101–113. https://doi.org/10.1161/CIRCRESAHA.118.313835

72.

Frangogiannis NG (2015) Pathophysiology of myocardial infarction. Compr Physiol 5:1841–1875. https://doi.org/10.1002/cphy.c150006

73.

Dongaonkar RM, Stewart RH, Geissler HJ, Laine GA (2010) Myocardial microvascular permeability, interstitial oedema, and compromised cardiac function. Cardiovasc Res 87:331–339. https://doi.org/10.1093/cvr/cvq145

74.

Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ (2007) The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 204:3037–3047. https://doi.org/10.1084/jem.20070885

75.

Dieterich LC, Seidel CD, Detmar M (2014) Lymphatic vessels: new targets for the treatment of inflammatory diseases. Angiogenesis 17:359–371. https://doi.org/10.1007/s10456-013-9406-1

76.

Vuorio T, Tirronen A, Ylä-Herttuala S (2017) Cardiac lymphatics - a new avenue for therapeutics? Trends Endocrinol Metab 28:285–296. https://doi.org/10.1016/j.tem.2016.12.002

77.

Chen XG, Lv YX, Zhao D, Zhang L, Zheng F, Yang JY, Li XL, Wang L, Guo LY, Pan YM, Yan YW, Chen SY, Wang JN, Tang JM, Wan Y (2016) Vascular endothelial growth factor-C protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis. Mol Cell Biochem 413:9–23. https://doi.org/10.1007/s11010-015-2622-9

78.

Lin QY, Zhang YL, Bai J, Liu JQ, Li HH (2021) VEGF-C/VEGFR-3 axis protects against pressure-overload induced cardiac dysfunction through regulation of lymphangiogenesis. Clin Transl Med 11:e374. https://doi.org/10.1002/ctm2.374

79.

Vieira JM, Norman S, Villa Del Campo C, Cahill TJ, Barnette DN, Gunadasa-Rohling M, Johnson LA, Greaves DR, Carr CA, Jackson DG, Riley PR (2018) The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. J Clin Invest 128:3402–3412. https://doi.org/10.1172/JCI97192

80.

Dorn LE, Petrosino JM, Wright P, Accornero F (2018) CTGF/CCN2 is an autocrine regulator of cardiac fibrosis. J Mol Cell Cardiol 121:205–211. https://doi.org/10.1016/j.yjmcc.2018.07.130

81.

Ishikawa Y, Akishima-Fukasawa Y, Ito K, Akasaka Y, Tanaka M, Shimokawa R, Kimura-Matsumoto M, Morita H, Sato S, Kamata I, Ishii T (2007) Lymphangiogenesis in myocardial remodelling after infarction. Histopathology 51:345–353. https://doi.org/10.1111/j.1365-2559.2007.02785.x

82.

Shimizu Y, Polavarapu R, Eskla KL, Pantner Y, Nicholson CK, Ishii M, Brunnhoelzl D, Mauria R, Husain A, Naqvi N, Murohara T, Calvert JW (2018)Impact of lymphangiogenesis on cardiac remodeling after ischemia and reperfusion injury. J Am Heart Assoc 7:e009565. https://doi.org/10.1161/JAHA.118.009565

83.

Maruyama K, Naemura K, Arima Y, Uchijima Y, Nagao H, Yoshihara K, Singh MK, Uemura A, Matsuzaki F, Yoshida Y, Kurihara Y, Miyagawa-Tomita S, Kurihara H (2021) Semaphorin3E-PlexinD1 signaling in coronary artery and lymphatic vessel development with clinical implications in myocardial recovery. iScience 24:102305. https://doi.org/10.1016/j.isci.2021.102305

84.

Liao S, Cheng G, Conner DA, Huang Y, Kucherlapati RS, Munn LL, Ruddle NH, Jain RK, Fukumura D, Padera TP (2011) Impaired lymphatic contraction associated with immunosuppression. Proc Natl Acad Sci U S A 108:18784–18789. https://doi.org/10.1073/pnas.1116152108

85.

Scallan JP, Zawieja SD, Castorena-Gonzalez JA, Davis MJ (2016) Lymphatic pumping: mechanics, mechanisms and malfunction. J Physiol 594:5749–5768. https://doi.org/10.1113/JP272088

86.

Angeli V, Ginhoux F, Llodrà J, Quemeneur L, Frenette PS, Skobe M, Jessberger R, Merad M, Randolph GJ (2006) B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24:203–215. https://doi.org/10.1016/j.immuni.2006.01.003

87.

Ji RC (2012) Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis. Cell Mol Life Sci 69:897–914. https://doi.org/10.1007/s00018-011-0848-6

88.

Swirski FK, Nahrendorf M (2013) Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 339:161–166. https://doi.org/10.1126/science.1230719

89.

Frangogiannis NG (2014) The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 11:255–265. https://doi.org/10.1038/nrcardio.2014.28

90.

Davis KL, Laine GA, Geissler HJ, Mehlhorn U, Brennan M, Allen SJ (2000) Effects of myocardial edema on the development of myocardial interstitial fibrosis. Microcirculation 7:269–280CrossRef

91.

Adapala RK, Kanugula AK, Paruchuri S, Chilian WM, Thodeti CK (2020) TRPV4 deletion protects heart from myocardial infarction-induced adverse remodeling via modulation of cardiac fibroblast differentiation. Basic Res Cardiol 115:14. https://doi.org/10.1007/s00395-020-0775-5

92.

Silvestre-Roig C, Fridlender ZG, Glogauer M, Scapini P (2019) Neutrophil diversity in health and disease. Trends Immunol 40:565–583. https://doi.org/10.1016/j.it.2019.04.012

93.

Beyer M, Mallmann MR, Xue J, Staratschek-Jox A, Vorholt D, Krebs W, Sommer D, Sander J, Mertens C, Nino-Castro A, Schmidt SV, Schultze JL (2012) High-resolution transcriptome of human macrophages. PLoS One 7:e45466. https://doi.org/10.1371/journal.pone.0045466

94.

Peet C, Ivetic A, Bromage DI, Shah AM (2020) Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc Res 116:1101–1112. https://doi.org/10.1093/cvr/cvz336

95.

Kologrivova I, Shtatolkina M, Suslova T, Ryabov V (2021) Cells of the immune system in cardiac remodeling: main players in resolution of inflammation and repair after myocardial infarction. Front Immunol 12:664457. https://doi.org/10.3389/fimmu.2021.664457

96.

Kim H, Kataru RP, Koh GY (2012) Regulation and implications of inflammatory lymphangiogenesis. Trends Immunol 33:350–356. https://doi.org/10.1016/j.it.2012.03.006

97.

Van der Borght K, Scott CL, Nindl V, Bouché A, Martens L, Sichien D, Van Moorleghem J, Vanheerswynghels M, De Prijck S, Saeys Y, Ludewig B, Gillebert T, Guilliams M, Carmeliet P, Lambrecht BN (2017) Myocardial infarction primes autoreactive T cells through activation of dendritic cells. Cell Rep 18:3005–3017. https://doi.org/10.1016/j.celrep.2017.02.079

98.

Liao YH, Cheng X (2006) Autoimmunity in myocardial infarction. Int J Cardiol 112:21–26. https://doi.org/10.1016/j.ijcard.2006.05.009

99.

Boag SE, Das R, Shmeleva EV, Bagnall A, Egred M, Howard N, Bennaceur K, Zaman A, Keavney B, Spyridopoulos I (2015) T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients. J Clin Invest 125:3063–3076. https://doi.org/10.1172/JCI80055

100.

Hofmann U, Frantz S (2016) Role of T-cells in myocardial infarction. Eur Heart J 37:873–879. https://doi.org/10.1093/eurheartj/ehv639

101.

Karadimou G, Gisterå A, Gallina AL, Caravaca AS, Centa M, Salagianni M, Andreakos E, Hansson GK, Malin S, Olofsson PS, Paulsson-Berne G (2020) Treatment with a Toll-like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice. J Intern Med 288:321–334. https://doi.org/10.1111/joim.13085

102.

Kutkut I, Meens MJ, McKee TA, Bochaton-Piallat ML, Kwak BR (2015) Lymphatic vessels: an emerging actor in atherosclerotic plaque development. Eur J Clin Invest 45:100–108. https://doi.org/10.1111/eci.12372

103.

Burger F, Miteva K, Baptista D, Roth A, Fraga-Silva RA, Martel C, Stergiopulos N, Mach F, Brandt KJ (2021) Follicular regulatory helper T cells control the response of regulatory B cells to a high-cholesterol diet. Cardiovasc Res 117:743–755. https://doi.org/10.1093/cvr/cvaa069

104.

Gu W, Ni Z, Tan YQ, Deng J, Zhang SJ, Lv ZC, Wang XJ, Chen T, Zhang Z, Hu Y, Jing ZC, Xu Q (2019) Adventitial cell atlas of wt (Wild Type) and ApoE (apolipoprotein E)-deficient mice defined by single-cell RNA sequencing. Arterioscler Thromb Vasc Biol 39:1055–1071. https://doi.org/10.1161/ATVBAHA.119.312399

105.

Tadayon S, Dunkel J, Takeda A, Eichin D, Virtakoivu R, Elima K, Jalkanen S, Hollmén M (2021) Lymphatic endothelial cell activation and dendritic cell transmigration is modified by genetic deletion of Clever-1. Front Immunol 12:602122. https://doi.org/10.3389/fimmu.2021.602122.

106.

Milasan A, Dallaire F, Mayer G, Martel C (2016) Effects of LDL receptor modulation on lymphatic function. Sci Rep 6:27862. https://doi.org/10.1038/srep27862

107.

Loo CP, Nelson NA, Lane RS, Booth JL, Loprinzi Hardin SC, Thomas A, Slifka MK, Nolz JC, Lund AW (2017) Lymphatic vessels balance viral dissemination and immune activation following cutaneous viral infection. Cell Rep 20:3176–3187. https://doi.org/10.1016/j.celrep.2017.09.006.

108.

Edwards LA, Nowocin AK, Jafari NV, Meader LL, Brown K, Sarde A, Lam C, Murray A, Wong W (2018) Chronic rejection of cardiac allografts is associated with increased lymphatic flow and cellular trafficking. Circulation 137:488–503. https://doi.org/10.1161/CIRCULATIONAHA.117.028533

109.

Stacker SA, Achen MG (2018) Emerging roles for VEGF-D in human disease. Biomolecules 8:1. https://doi.org/10.3390/biom8010001

110.

Cursiefen C, Cao J, Chen L, Liu Y, Maruyama K, Jackson D, Kruse FE, Wiegand SJ, Dana MR, Streilein JW (2004) Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest Ophthalmol Vis Sci 45:2666–2673. https://doi.org/10.1167/iovs.03-1380

111.

Jones D, Min W (2011) An overview of lymphatic vessels and their emerging role in cardiovascular disease. J Cardiovasc Dis Res 2:141–152. https://doi.org/10.4103/0975-3583.85260

112.

Jonigk D, Lehmann U, Stuht S, Wilhelmi M, Haverich A, Kreipe H, Mengel M (2007) Recipient-derived neoangiogenesis of arterioles and lymphatics in quilty lesions of cardiac allografts. Transplantation 84:1335–1342. https://doi.org/10.1097/01.tp.0000287458.72440.75

113.

Brown K, Badar A, Sunassee K, Fernandes MA, Shariff H, Jurcevic S, Blower PJ, Sacks SH, Mullen GE, Wong W (2011) SPECT/CT lymphoscintigraphy of heterotopic cardiac grafts reveals novel sites of lymphatic drainage and T cell priming. Am J Transplant 11:225–234. https://doi.org/10.1111/j.1600-6143.2010.03388.x

114.

Daly KP, Seifert ME, Chandraker A, Zurakowski D, Nohria A, Givertz MM, Karumanchi SA, Briscoe DM (2013) VEGF-C, VEGF-A and related angiogenesis factors as biomarkers of allograft vasculopathy in cardiac transplant recipients. J Heart Lung Transplant 32:120–128. https://doi.org/10.1016/j.healun.2012.09.030

115.

Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, Soleiman A, Birner P, Krieger S, Hovorka A, Silberhumer G, Laakkonen P, Petrova T, Langer B, Raab I (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 15:603–612. https://doi.org/10.1097/01.asn.0000113316.52371.2e

116.

Stehlik J, Armstrong B, Baran DA, Bridges ND, Chandraker A, Gordon R, De Marco T, Givertz MM, Heroux A, Iklé D, Hunt J, Kfoury AG, Madsen JC, Morrison Y, Feller E, Pinney S, Tripathi S, Heeger PS, Starling RC (2019) Early immune biomarkers and intermediate-term outcomes after heart transplantation: results of Clinical Trials in Organ Transplantation-18. Am J Transplant 19:1518–1528. https://doi.org/10.1111/ajt.15218

117.

Krebs R, Tikkanen JM, Ropponen JO, Jeltsch M, Jokinen JJ, Ylä-Herttuala S, Nykänen AI, Lemström KB (2012) Critical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis. Am J Pathol 181:1607–1620. https://doi.org/10.1016/j.ajpath.2012.07.021

118.

Emami-Naeini P, Dohlman TH, Omoto M, Hattori T, Chen Y, Lee HS, Chauhan SK, Dana R (2014) Soluble vascular endothelial growth factor receptor-3 suppresses allosensitization and promotes corneal allograft survival. Graefes Arch Clin Exp Ophthalmol 252:1755–1762. https://doi.org/10.1007/s00417-014-2749-5

119.

Yin N, Zhang N, Xu J, Shi Q, Ding Y, Bromberg JS (2011) Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival. Transplantation 92:25–30. https://doi.org/10.1097/TP.0b013e31821d2661

120.

Hos D, Matthaei M, Bock F, Maruyama K, Notara M, Clahsen T, Hou Y, Le VNH, Salabarria AC, Horstmann J, Bachmann BO, Cursiefen C (2019) Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation. Prog Retin Eye Res 73:100768. https://doi.org/10.1016/j.preteyeres.2019.07.001

121.

Podgrabinska S, Kamalu O, Mayer L, Shimaoka M, Snoeck H, Randolph GJ, Skobe M (2009) Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. J Immunol 183:1767–1779. https://doi.org/10.4049/jimmunol.0802167

122.

Card CM, Yu SS, Swartz MA (2014) Emerging roles of lymphatic endothelium in regulating adaptive immunity. J Clin Invest 124:943–952. https://doi.org/10.1172/JCI73316

123.

Dohlman TH, Omoto M, Hua J, Stevenson W, Lee SM, Chauhan SK, Dana R (2015) VEGF-trap aflibercept significantly improves long-term graft survival in high-risk corneal transplantation. Transplantation 99:678–686. https://doi.org/10.1097/TP.0000000000000512

124.

Azzi J, Yin Q, Uehara M, Ohori S, Tang L, Cai K, Ichimura T, McGrath M, Maarouf O, Kefaloyianni E, Loughhead S, Petr J, Sun Q, Kwon M, Tullius S, von Andrian UH, Cheng J, Abdi R (2016) Targeted delivery of immunomodulators to lymph nodes. Cell Rep 15:1202–1213. https://doi.org/10.1016/j.celrep.2016.04.007

125.

Yamagami S, Dana MR, Tsuru T (2002) Draining lymph nodes play an essential role in alloimmunity generated in response to high-risk corneal transplantation. Cornea 21:405–409. https://doi.org/10.1097/00003226-200205000-00014

126.

Li W, Gauthier JM, Tong AY, Terada Y, Higashikubo R, Frye CC, Harrison MS, Hashimoto K, Bery AI, Ritter JH, Nava RG, Puri V, Wong BW, Lavine KJ, Bharat A, Krupnick AS, Gelman AE, Kreisel D (2020) Lymphatic drainage from bronchus-associated lymphoid tissue in tolerant lung allografts promotes peripheral tolerance. J Clin Invest 130:6718–6727. https://doi.org/10.1172/JCI136057

127.

Cui Y, Liu K, Monzon-Medina ME, Padera RF, Wang H, George G, Toprak D, Abdelnour E, D'Agostino E, Goldberg HJ, Perrella MA, Forteza RM, Rosas IO, Visner G, El-Chemaly S (2015) Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection. J Clin Invest 125:4255–4268. https://doi.org/10.1172/JCI79693

128.

Nielsen NR, Rangarajan KV, Mao L, Rockman HA, Caron KM (2020) A murine model of increased coronary sinus pressure induces myocardial edema with cardiac lymphatic dilation and fibrosis. Am J Physiol Heart Circ Physiol 318:H895-H907. https://doi.org/10.1152/ajpheart.00436.2019

129.

Berta J, Hoda MA, Laszlo V, Rozsas A, Garay T, Torok S, Grusch M, Berger W, Paku S, Renyi-Vamos F, Masri B, Tovari J, Groger M, Klepetko W, Hegedus B, Dome B (2014) Apelin promotes lymphangiogenesis and lymph node metastasis. Oncotarget 5:4426–4437. https://doi.org/10.18632/oncotarget.2032

130.

Ashley EA, Powers J, Chen M, Kundu R, Finsterbach T, Caffarelli A, Deng A, Eichhorn J, Mahajan R, Agrawal R, Greve J, Robbins R, Patterson AJ, Bernstein D, Quertermous T (2005) The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc Res 65:73–82. https://doi.org/10.1016/j.cardiores.2004.08.018

131.

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

132.

Zhang HF, Wang YL, Tan YZ, Wang HJ, Tao P, Zhou P (2019) Enhancement of cardiac lymphangiogenesis by transplantation of CD34(+)VEGFR-3(+) endothelial progenitor cells and sustained release of VEGF-C. Basic Res Cardiol 114:43. https://doi.org/10.1007/s00395-019-0752-z

133.

Wang YL, Yu SN, Shen HR, Wang HJ, Wu XP, Wang QL, Zhou B, Tan YZ (2021) Thymosin β4 released from functionalized self-assembling peptide activates epicardium and enhances repair of infarcted myocardium. Theranostics 11:4262–4280. https://doi.org/10.7150/thno.52309. eCollection 2021

134.

Liu X, Pasula S, Song H, Tessneer KL, Dong Y, Hahn S, Yago T, Brophy ML, Chang B, Cai X, Wu H, McManus J, Ichise H, Georgescu C, Wren JD, Griffin C, Xia L, Srinivasan RS, Chen H (2014) Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function. Sci Signal 7:ra97. https://doi.org/10.1126/scisignal.2005413

135.

Wu H, Rahman HNA, Dong Y, Liu X, Lee Y, Wen A, To KH, Xiao L, Birsner AE, Bazinet L, Wong S, Song K, Brophy ML, Mahamud MR, Chang B, Cai X, Pasula S, Kwak S, Yang W, Bischoff J, Xu J, Bielenberg DR, Dixon JB, D'Amato RJ, Srinivasan RS, Chen H (2018) Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes. J Clin Invest 128:4025–4043. https://doi.org/10.1172/JCI96063

136.

Korpela H, Järveläinen N, Siimes S, Lampela J, Airaksinen J, Valli K, Turunen M, Pajula J, Nurro J, Ylä-Herttuala S (2021) Gene therapy for ischaemic heart disease and heart failure. J Intern Med. https://doi.org/10.1111/joim.13308 Online ahead of print

Title: The role of lymphangiogenesis in cardiovascular diseases and heart transplantation
Author: Rui-Cheng Ji
Publication date: 04-11-2021
Publisher: Springer US
Keywords: Heart Transplantation
Myocardial Infarction
Heart Transplantation
Heart Transplantation
Arterial Occlusive Disease
Heart Transplantation
Heart Transplantation
Published in: Heart Failure Reviews / Issue 5/2022
Print ISSN: 1382-4147
Electronic ISSN: 1573-7322
DOI: https://doi.org/10.1007/s10741-021-10188-5

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