Establishment and maintenance of blood–lymph separation

  • Harish P. Janardhan
  • Chinmay M. TrivediEmail author


Hippocratic Corpus, a collection of Greek medical literature, described the functional anatomy of the lymphatic system in the fifth century B.C. Subsequent studies in cadavers and surgical patients firmly established that lymphatic vessels drain extravasated interstitial fluid, also known as lymph, into the venous system at the bilateral lymphovenous junctions. Recent advances revealed that lymphovenous valves and platelet-mediated hemostasis at the lymphovenous junctions maintain life-long separation of the blood and lymphatic vascular systems. Here, we review murine models that exhibit failure of blood–lymph separation to highlight the novel mechanisms and molecular targets for the modulation of lymphatic disorders. Specifically, we focus on the transcription factors, cofactors, and signaling pathways that regulate lymphovenous valve development and platelet-mediated lymphovenous hemostasis, which cooperate to maintain blood–lymph separation.


Lymphovenous valve Hemostasis Platelet Lymphatic development Lymph Blood 



We gratefully acknowledge Zachary J. Milstone for critical reading of the article. C.M.T is supported by National Heart, Lung, and Blood Institute grants R01 HL141377 (to C.M.T). We apologize to our colleagues whose work could not be discussed due to space limitations.

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interest exists.


  1. 1.
    Risau W, Flamme I (1995) Vasculogenesis. Annu Rev Cell Dev Biol 11:73–91. CrossRefPubMedGoogle Scholar
  2. 2.
    Drake CJ, Fleming PA (2000) Vasculogenesis in the day 6.5 to 9.5 mouse embryo. Blood 95:1671–1679PubMedGoogle Scholar
  3. 3.
    Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146:873–887. CrossRefPubMedGoogle Scholar
  4. 4.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674. CrossRefGoogle Scholar
  5. 5.
    Bautch VL, Caron KM (2015) Blood and lymphatic vessel formation. Cold Spring Harb Perspect Biol 7:a008268. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478. CrossRefPubMedGoogle Scholar
  7. 7.
    Simons M, Eichmann A (2013) Lymphatics are in my veins. Science 341:622–624. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140:460–476. CrossRefPubMedGoogle Scholar
  9. 9.
    Loukas M, Bellary SS, Kuklinski M et al (2011) The lymphatic system: a historical perspective. Clin Anat 24:807–816. CrossRefPubMedGoogle Scholar
  10. 10.
    Sabin FR (1909) The lymphatic system in human embryos, with a consideration of the morphology of the system as a whole. Am J Anat 9:43–91. CrossRefGoogle Scholar
  11. 11.
    Huntington GS, McClure CFW (1910) The anatomy and development of the jugular lymph sacs in the domestic cat (Felis domestica). Am J Anat 10:177–312. CrossRefGoogle Scholar
  12. 12.
    Srinivasan RS, Dillard ME, Lagutin OV et al (2007) Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev 21:2422–2432. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Klotz L, Norman S, Vieira JM et al (2015) Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature 522:62–67. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Stanczuk L, Martinez-Corral I, Ulvmar MH et al (2015) cKit lineage hemogenic endothelium-derived cells contribute to mesenteric lymphatic vessels. Cell Rep 10:1708–1721. CrossRefGoogle Scholar
  15. 15.
    Martinez-Corral I, Ulvmar MH, Stanczuk L et al (2015) Nonvenous origin of dermal lymphatic vasculature. Circ Res 116:1649–1654. CrossRefPubMedGoogle Scholar
  16. 16.
    Petrova TV, Koh GY (2018) Organ-specific lymphatic vasculature: from development to pathophysiology. J Exp Med 215:35–49. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ulvmar MH, Makinen T (2016) Heterogeneity in the lymphatic vascular system and its origin. Cardiovasc Res 111:310–321. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Uebelhoer M, Boon LM, Vikkula M (2012) Vascular anomalies: from genetics toward models for therapeutic trials. Cold Spring Harb Perspect Med 2:a009688–a009688. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wassef M, Blei F, Adams D et al (2015) Vascular anomalies classification: recommendations from the international society for the study of vascular anomalies. Pediatrics 136(1):e203–e214. CrossRefPubMedGoogle Scholar
  20. 20.
    Swartz MA (2001) The physiology of the lymphatic system. Adv Drug Deliv Rev 50:3–20. CrossRefPubMedGoogle Scholar
  21. 21.
    Bernier-Latmani J (2017) Petrova TV (2017) Intestinal lymphatic vasculature: structure, mechanisms and functions. Nat Rev Gastroenterol Hepatol 14(9):510–526. CrossRefPubMedGoogle Scholar
  22. 22.
    Smith ME, Riffat F, Jani P (2013) The surgical anatomy and clinical relevance of the neglected right lymphatic duct: review. J Laryngol Otol 127:128–133. CrossRefPubMedGoogle Scholar
  23. 23.
    Ratnayake CBB, Escott ABJ, Phillips ARJ, Windsor JA (2018) The anatomy and physiology of the terminal thoracic duct and ostial valve in health and disease: potential implications for intervention. J Anat 233:1–14. CrossRefPubMedGoogle Scholar
  24. 24.
    Ushiwata I, Ushiki T (1990) Cytoarchitecture of the smooth muscles and pericytes of rat cerebral blood vessels. A scanning electron microscopic study. J Neurosurg 73:82–90. CrossRefPubMedGoogle Scholar
  25. 25.
    Kinnaert P (1973) Anatomical variations of the cervical portion of the thoracic duct in man. J Anat 115:45–52PubMedPubMedCentralGoogle Scholar
  26. 26.
    Langford RJ, Daudia AT, Malins TJ (1999) A morphological study of the thoracic duct at the jugulo-subclavian junction. J Craniomaxillofac Surg 27:100–104. CrossRefPubMedGoogle Scholar
  27. 27.
    Yalakurthi S, Vishnumukkala TR, Siri CC et al (2013) Anatomical variations of the termination of the thoracic duct in humans. Int J Med Health Sci 2:230–234Google Scholar
  28. 28.
    Davis HK (1915) A statistical study of the thoracic duct in man. Am J Anat 17:211–244. CrossRefGoogle Scholar
  29. 29.
    Shimada K, Sato I (1997) Morphological and histological analysis of the thoracic duct at the jugulo-subclavian junction in Japanese cadavers. Clin Anat 10:163–172.;2-v CrossRefPubMedGoogle Scholar
  30. 30.
    Seeger M, Bewig B, Günther R et al (2009) Terminal part of thoracic duct: high-resolution US imaging. Radiology 252:897–904. CrossRefPubMedGoogle Scholar
  31. 31.
    Calnan JS, Pflug JJ, Reis ND, Taylor LM (1970) Lymphatic pressures and the flow of lymph. Br J Plast Surg 23:305–317CrossRefPubMedGoogle Scholar
  32. 32.
    Pflug J, Calnan J (1968) The valves of the thoracic duct at the angulus venosus. Br J Surg 55:911–916. CrossRefPubMedGoogle Scholar
  33. 33.
    Parasher VK, Meroni E, Spinelli P (1995) Anatomy of the thoracic duct: an endosonographic study. Gastrointest Endosc 42:188–189. CrossRefPubMedGoogle Scholar
  34. 34.
    Srinivasan RS, Oliver G (2011) Prox1 dosage controls the number of lymphatic endothelial cell progenitors and the formation of the lymphovenous valves. Genes Dev 25:2187–2197. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Geng X, Cha B, Mahamud MR et al (2016) Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development. Dev Biol 409:218–233. CrossRefPubMedGoogle Scholar
  36. 36.
    Yang Y, Oliver G (2014) Development of the mammalian lymphatic vasculature. J Clin Investig 124:888–897. CrossRefPubMedGoogle Scholar
  37. 37.
    Bowles J, Secker G, Nguyen C et al (2014) Control of retinoid levels by CYP26B1 is important for lymphatic vascular development in the mouse embryo. Dev Biol 386:25–33. CrossRefPubMedGoogle Scholar
  38. 38.
    Cha B, Geng X, Mahamud MR et al (2016) Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves. Genes Dev 30:1454–1469. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Turner CJ, Badu-Nkansah K, Crowley D et al (2014) Integrin-α5β1 is not required for mural cell functions during development of blood vessels but is required for lymphatic–blood vessel separation and lymphovenous valve formation. Dev Biol 392:381–392. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Janardhan HP, Milstone ZJ, Shin M et al (2017) Hdac3 regulates lymphovenous and lymphatic valve formation. J Clin Investig 127:4193–4206. CrossRefPubMedGoogle Scholar
  41. 41.
    Kazenwadel J, Betterman KL, Chong C-E et al (2015) GATA2 is required for lymphatic vessel valve development and maintenance. J Clin Investig 125:2979–2994. CrossRefPubMedGoogle Scholar
  42. 42.
    Martin-Almedina S, Martinez-Corral I, Holdhus R et al (2016) EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis. J Clin Investig 126:3080–3088. CrossRefPubMedGoogle Scholar
  43. 43.
    Fang J, Dagenais SL, Erickson RP et al (2000) Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema–distichiasis syndrome. Am J Hum Genet 67:1382–1388. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Petrova TV, Karpanen T, Norrmén C et al (2004) Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med 10:974–981. CrossRefPubMedGoogle Scholar
  45. 45.
    Sabine A, Agalarov Y, Maby-El Hajjami H et al (2012) Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. Dev Cell 22:430–445. CrossRefPubMedGoogle Scholar
  46. 46.
    Kanady JD, Munger SJ, Witte MH, Simon AM (2015) Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling. Dev Biol 405:33–46. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kanady JD, Dellinger MT, Munger SJ et al (2011) Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax. Dev Biol 354:253–266. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Meens MJ, Sabine A, Petrova TV, Kwak BR (2014) Connexins in lymphatic vessel physiology and disease. FEBS Lett 588:1271–1277. CrossRefPubMedGoogle Scholar
  49. 49.
    Karpinich NO, Caron KM (2015) Gap junction coupling is required for tumor cell migration through lymphatic endothelium. Arterioscler Thromb Vasc Biol 35:1147–1155. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kanady JD, Simon AM (2011) Lymphatic communication: connexin junction, what’s your function? Lymphology 44:95–102PubMedPubMedCentralGoogle Scholar
  51. 51.
    Huang GY, Cooper ES, Waldo K et al (1998) Gap junction-mediated cell–cell communication modulates mouse neural crest migration. J Cell Biol 143:1725–1734. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ostergaard P, Simpson MA, Connell FC et al (2011) Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet 43:929–931. CrossRefPubMedGoogle Scholar
  53. 53.
    Kazenwadel J, Secker GA, Liu YJ et al (2012) Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood 119:1283–1291. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Spinner MA, Sanchez LA, Hsu AP et al (2014) GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123:809–821. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Hsu AP, Johnson KD, Falcone EL et al (2013) GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood 121:3830–3837. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Ganapathi KA, Townsley DM, Hsu AP et al (2015) GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia. Blood 125:56–70. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Johnson KD, Hsu AP, Ryu M-J et al (2012) Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity. J Clin Investig 122:3692–3704. CrossRefPubMedGoogle Scholar
  58. 58.
    Wozniak RJ, Boyer ME, Grass JA et al (2007) Context-dependent GATA factor function. J Biol Chem 282:14665–14674. CrossRefPubMedGoogle Scholar
  59. 59.
    Lim K-C, Hosoya T, Brandt W et al (2012) Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning. J Clin Investig 122:3705–3717. CrossRefPubMedGoogle Scholar
  60. 60.
    Khandekar M, Brandt W, Zhou Y et al (2007) A Gata2 intronic enhancer confers its pan-endothelia-specific regulation. Development 134:1703–1712. CrossRefPubMedGoogle Scholar
  61. 61.
    Taniguchi K, Kohno R-I, Ayada T et al (2007) Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. Mol Cell Biol 27:4541–4550. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Deng Y, Atri D, Eichmann A, Simons M (2013) Endothelial ERK signaling controls lymphatic fate specification. J Clin Investig 123:1202–1215. CrossRefPubMedGoogle Scholar
  63. 63.
    Murtomaki A, Uh MK, Choi YK et al (2013) Notch1 functions as a negative regulator of lymphatic endothelial cell differentiation in the venous endothelium. Development 140:2365–2376. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Murtomaki A, Uh MK, Kitajewski C et al (2014) Notch signaling functions in lymphatic valve formation. Development 141:2446–2451. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Outeda P, Huso DL, Fisher SA et al (2014) Polycystin signaling is required for directed endothelial cell migration and lymphatic development. Cell Rep 7:634–644. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Cha B, Geng X, Mahamud MR et al (2018) Complementary Wnt sources regulate lymphatic vascular development via PROX1-dependent Wnt/β-catenin signaling. Cell Rep 25:571–584.e5. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Loirand G, Sauzeau V, Pacaud P (2013) Small G proteins in the cardiovascular system: physiological and pathological aspects. Physiol Rev 93:1659–1720. CrossRefPubMedGoogle Scholar
  68. 68.
    Garrett TA, van Buul JD, Burridge K (2007) VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2. Exp Cell Res 313:3285–3297CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Zeng H, Zhao D, Mukhopadhyay D (2002) KDR stimulates endothelial cell migration through heterotrimeric G protein Gq/11-mediated activation of a small GTPase RhoA. J Biol Chem 277:46791–46798. CrossRefPubMedGoogle Scholar
  70. 70.
    D’Amico G, Jones DT, Nye E et al (2009) Regulation of lymphatic–blood vessel separation by endothelial Rac1. Development 136:4043–4053. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Liu X, Gu X, Ma W et al (2018) Rasip1 controls lymphatic vessel lumen maintenance by regulating endothelial cell junctions. Development 145:dev165092. CrossRefPubMedGoogle Scholar
  72. 72.
    Xu W, Wittchen ES, Hoopes SL et al (2018) Small GTPase Rap1A/B is required for lymphatic development and adrenomedullin-induced stabilization of lymphatic endothelial junctions. Arterioscler Thromb Vasc Biol.;pagegroup:string:publication CrossRefPubMedGoogle Scholar
  73. 73.
    Kimberling WJ, Fain PR, Kenyon JB et al (1988) Linkage heterogeneity of autosomal dominant polycystic kidney disease. N Engl J Med 319:913–918. CrossRefPubMedGoogle Scholar
  74. 74.
    Romeo G, Costa G, Catizone L et al (1988) A second genetic locus for autosomal dominant polycystic kidney disease. Lancet 332:8–11. CrossRefGoogle Scholar
  75. 75.
    Coxam B, Sabine A, Bower NI et al (2014) Pkd1 regulates lymphatic vascular morphogenesis during development. Cell Rep 7:623–633CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Bellini C, Donarini G, Paladini D et al (2015) Etiology of non-immune hydrops fetalis: an update. Am J Med Genet 167:1082–1088. CrossRefGoogle Scholar
  77. 77.
    Mackie DI, Mutairi Al F, Davis RB et al (2018) hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. J Exp Med 215:2339–2353. CrossRefPubMedGoogle Scholar
  78. 78.
    Alders M, Al-Gazali L, Cordeiro I et al (2014) Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome—PubMed-NCBI. Hum Genet 133:1161–1167. CrossRefPubMedGoogle Scholar
  79. 79.
    Alders M, Hogan BM, Gjini E et al (2009) Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet 41:1272–1274. CrossRefPubMedGoogle Scholar
  80. 80.
    Fotiou E, Martin-Almedina S, Simpson MA et al (2015) Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis. Nat Commun 6:8085. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Shah S, Conlin LK, Gomez L et al (2013) CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops. PLoS One 8:e75770. CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Avraamides CJ, Garmy-Susini B, Varner JA (2008) Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8:604–617. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Chen J, Alexander JS, Orr AW (2012) Integrins and their extracellular matrix ligands in lymphangiogenesis and lymph node metastasis. Int J Cell Biol 2012:1–12. CrossRefGoogle Scholar
  84. 84.
    Hess PR, Rawnsley DR, Jakus Z et al (2014) Platelets mediate lymphovenous hemostasis to maintain blood–lymphatic separation throughout life. J Clin Investig 124:273–284. CrossRefPubMedGoogle Scholar
  85. 85.
    Vigl B, Zgraggen C, Rehman N et al (2009) Coxsackie- and adenovirus receptor (CAR) is expressed in lymphatic vessels in human skin and affects lymphatic endothelial cell function in vitro. Exp Cell Res 315:336–347. CrossRefPubMedGoogle Scholar
  86. 86.
    Mirza M, Pang M-F, Zaini MA et al (2012) Essential role of the coxsackie—and adenovirus receptor (CAR) in development of the lymphatic system in mice. PLoS One 7:e37523. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Abtahian F, Guerriero A, Sebzda E et al (2003) Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299:247–251. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Bertozzi CC, Schmaier AA, Mericko P et al (2010) Platelets regulate lymphatic vascular development through CLEC-2–SLP-76 signaling. Blood 116:661–670. CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Sebzda E, Hibbard C, Sweeney S et al (2006) Syk and Slp-76 Mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development. Dev Cell 11:349–361. CrossRefPubMedGoogle Scholar
  90. 90.
    Suzuki-Inoue K, Kato Y, Inoue O et al (2007) Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 282:25993–26001. CrossRefPubMedGoogle Scholar
  91. 91.
    Suzuki-Inoue K, Fuller GLJ, García A et al (2006) A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 107:542–549. CrossRefPubMedGoogle Scholar
  92. 92.
    Finney BA, Schweighoffer E, Navarro-Nuñez L et al (2012) CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development. Blood 119:1747–1756. CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Suzuki-Inoue K, Inoue O, Ding G et al (2010) Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. J Biol Chem 285:24494–24507. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Herzog BH, Fu J, Wilson SJ et al (2013) Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature 502:105–109CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Uhrin P, Zaujec J, Breuss JM et al (2010) Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood 115:3997–4005. CrossRefPubMedGoogle Scholar
  96. 96.
    Ichise H, Ichise T, Ohtani O, Yoshida N (2009) Phospholipase Cgamma2 is necessary for separation of blood and lymphatic vasculature in mice. Development 136:191–195. CrossRefPubMedGoogle Scholar
  97. 97.
    Kato Y, Kaneko MK, Kunita A et al (2008) Molecular analysis of the pathophysiological binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-2. Cancer Sci 99:54–61. CrossRefPubMedGoogle Scholar
  98. 98.
    May F, Hagedorn I, Pleines I et al (2009) CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood 114:3464–3472. CrossRefPubMedGoogle Scholar
  99. 99.
    Fuller GLJ, Williams JAE, Tomlinson MG et al (2007) The C-type lectin receptors CLEC-2 and Dectin-1, but not DC-SIGN, signal via a novel YXXL-dependent signaling cascade. J Biol Chem 282:12397–12409. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Spalton JC, Mori J, Pollitt AY et al (2009) The novel Syk inhibitor R406 reveals mechanistic differences in the initiation of GPVI and CLEC-2 signaling in platelets. J Thromb Haemost 7:1192–1199. CrossRefPubMedGoogle Scholar
  101. 101.
    Séverin S, Pollitt AY, Navarro-Nuñez L et al (2011) Syk-dependent phosphorylation of CLEC-2 a novel mechanism of hem-immunoreceptor tyrosine-based activation motif signaling. J Biol Chem 286:4107–4116. CrossRefPubMedGoogle Scholar
  102. 102.
    Carramolino L, Fuentes J, García-Andrés C et al (2010) Platelets play an essential role in separating the blood and lymphatic vasculatures during embryonic angiogenesis. Circ Res 106:1197–1201CrossRefPubMedGoogle Scholar
  103. 103.
    Manne BK, Badolia R, Dangelmaier C et al (2015) Distinct pathways regulate Syk protein activation downstream of immune tyrosine activation motif (ITAM) and hemITAM receptors in platelets. J Biol Chem 290:11557–11568. CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Zhang Y, Daubel N, Stritt S, Makinen T (2018) Transient loss of venous integrity during developmental vascular remodeling leads to red blood cell extravasation and clearance by lymphatic vessels. Development 145:dev156745. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Fu J, Gerhardt H, McDaniel JM et al (2008) Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J Clin Investig 118:3725–3737. CrossRefPubMedGoogle Scholar
  106. 106.
    Bianchi R, Russo E, Bachmann SB et al (2017) 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. CrossRefPubMedGoogle Scholar
  107. 107.
    Crosswhite PL, Podsiadlowska JJ, Curtis CD et al (2016) CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity. J Clin Investig 126:2254–2266. CrossRefPubMedGoogle Scholar
  108. 108.
    Welsh JD, Kahn ML, Sweet DT (2016) Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation. Blood 128:1169–1173. CrossRefPubMedGoogle Scholar
  109. 109.
    Chen C-Y, Bertozzi C, Zou Z et al (2012) Blood flow reprograms lymphatic vessels to blood vessels. J Clin Investig 122:2006–2017. CrossRefPubMedGoogle Scholar
  110. 110.
    Kiefer F, Brumell J, Al-Alawi N et al (1998) The Syk protein tyrosine kinase is essential for Fcγ receptor signaling in macrophages and neutrophils. Mol Cell Biol 18:4209–4220. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Turner M, Mee PJ, Costello PS et al (1995) Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 378:298–302. CrossRefPubMedGoogle Scholar
  112. 112.
    Cheng AM, Rowley B, Pao W et al (1995) Syk tyrosine kinase required for mouse viability and B-cell development. Nature 378:303–306. CrossRefPubMedGoogle Scholar
  113. 113.
    Sweet DT, Jiménez JM, Chang J et al (2015) Lymph flow regulates collecting lymphatic vessel maturation in vivo. J Clin Investig 125:2995–3007. CrossRefPubMedGoogle Scholar
  114. 114.
    Bäckhed F, Crawford PA, O’Donnell D, Gordon JI (2007) Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor. Proc Natl Acad Sci USA 104:606–611. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Cardiovascular MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA
  3. 3.Department of Molecular, Cell, and Cancer BiologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  4. 4.The Li-Weibo Institute for Rare Diseases ResearchUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations