The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease
2020; Cell Press; Volume: 182; Issue: 2 Linguagem: Inglês
10.1016/j.cell.2020.06.039
ISSN1097-4172
AutoresGuillermo Oliver, Jonathan Kipnis, Gwendalyn J. Randolph, Natasha L. Harvey,
Tópico(s)Systemic Sclerosis and Related Diseases
ResumoMammals have two specialized vascular circulatory systems: the blood vasculature and the lymphatic vasculature. The lymphatic vasculature is a unidirectional conduit that returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays major roles in immune cell trafficking and lipid absorption. As we discuss in this review, the molecular characterization of lymphatic vascular development and our understanding of this vasculature’s role in pathophysiological conditions has greatly improved in recent years, changing conventional views about the roles of the lymphatic vasculature in health and disease. Morphological or functional defects in the lymphatic vasculature have now been uncovered in several pathological conditions. We propose that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body’s response to a wide range of human diseases. Mammals have two specialized vascular circulatory systems: the blood vasculature and the lymphatic vasculature. The lymphatic vasculature is a unidirectional conduit that returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays major roles in immune cell trafficking and lipid absorption. As we discuss in this review, the molecular characterization of lymphatic vascular development and our understanding of this vasculature’s role in pathophysiological conditions has greatly improved in recent years, changing conventional views about the roles of the lymphatic vasculature in health and disease. Morphological or functional defects in the lymphatic vasculature have now been uncovered in several pathological conditions. We propose that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body’s response to a wide range of human diseases. Although blood vessels are essential for oxygen and nutrient delivery and disposal of waste products for detoxification and replenishment, the lymphatic vasculature plays essential roles in immune surveillance, lipid absorption, and maintenance of tissue fluid balance (Oliver, 2004Oliver G. Lymphatic vasculature development.Nat. Rev. Immunol. 2004; 4: 35-45Crossref PubMed Google Scholar; Oliver and Alitalo, 2005Oliver G. Alitalo K. The lymphatic vasculature: recent progress and paradigms.Annu. Rev. Cell Dev. Biol. 2005; 21: 457-483Crossref PubMed Scopus (150) Google Scholar; Petrova and Koh, 2018Petrova T.V. Koh G.Y. Organ-specific lymphatic vasculature: From development to pathophysiology.J. Exp. Med. 2018; 215: 35-49Crossref PubMed Scopus (75) Google Scholar; Tammela and Alitalo, 2010Tammela T. Alitalo K. Lymphangiogenesis: Molecular mechanisms and future promise.Cell. 2010; 140: 460-476Abstract Full Text Full Text PDF PubMed Scopus (832) Google Scholar). The cellular and molecular characterization of lymphatic vascular development and our understanding of this vasculature’s role in pathophysiological conditions has greatly improved in recent years, changing conventional views about its functional roles in health and disease. Traditionally considered a passive route for transport of fluid, immune cells, and lipoproteins, lymphatics are now known to be active players in major physiological and pathophysiological processes. Until recently, lymphatic vessel dysfunction was mainly associated with primary and secondary lymphedema. Unexpectedly, however, lymphatic vascular defects have been uncovered in conditions such as obesity, cardiovascular disease, inflammation, hypertension, atherosclerosis, Crohn’s disease, glaucoma and various neurological disorders such as Alzheimer’s disease. In this review, we first provide a brief overview of lymphatic anatomy and of the key molecular and morphological steps underlying formation of the mammalian lymphatic vasculature. Next we discuss the long-standing conventional views regarding lymphatic function in normal (immune surveillance) and disease conditions (tumor progression and symptomatic lymphatic disorders). Finally, we assess recent discoveries revealing novel roles of the lymphatic vasculature in a variety of human disorders; these findings support our hypothesis that subtle asymptomatic morphological and/or functional alterations in the lymphatic vasculature are responsible for the variability seen in the body’s response to a range of pathological conditions. The lymphatic vasculature consists of a network of thin-walled, blind-ended, highly permeable initial lymphatics (also called lymphatic capillaries, although they are functionally distinct from blood vascular capillaries) and larger collecting lymphatic vessels (Figure 1). Initial lymphatics consist of a single layer of loosely connected lymphatic endothelial cells (LECs) that lack a continuous basement membrane and perivascular mural cells, such as pericytes and smooth muscle cells (Figure 1). LECs within initial lymphatics are inter-connected through discontinuous button-like junctions (Figure 1; Baluk et al., 2007Baluk P. Fuxe J. Hashizume H. Romano T. Lashnits E. Butz S. Vestweber D. Corada M. Molendini C. Dejana E. McDonald D.M. Functionally specialized junctions between endothelial cells of lymphatic vessels.J. Exp. Med. 2007; 204: 2349-2362Crossref PubMed Scopus (522) Google Scholar) that facilitate uptake of interstitial fluid and macromolecules. Blood plasma is continuously filtered from the arterial side of the capillary bed into the interstitial space, where excess fluid and macromolecules are taken up by initial lymphatics (Alitalo, 2011Alitalo K. The lymphatic vasculature in disease.Nat. Med. 2011; 17: 1371-1380Crossref PubMed Scopus (516) Google Scholar). Initial lymphatics interact with the extracellular matrix through anchoring filaments that facilitate sensing of changes in interstitial pressure, which, in turn, modulates opening of “flap valves” between the button junctions to allow fluid entry (Tammela and Alitalo, 2010Tammela T. Alitalo K. Lymphangiogenesis: Molecular mechanisms and future promise.Cell. 2010; 140: 460-476Abstract Full Text Full Text PDF PubMed Scopus (832) Google Scholar; Figure 1). All of these features make the initial lymphatic vessels highly permeable to large macromolecules, pathogens, and immune cells. Initial lymphatics first drain into pre-collecting lymphatic vessels that merge with larger secondary collecting lymphatics, in which LECs are connected to each other through tighter, continuous zipper-like junctions and covered with specialized muscle cells that provide contractile activity to assist lymph flow (Figure 1; Baluk et al., 2007Baluk P. Fuxe J. Hashizume H. Romano T. Lashnits E. Butz S. Vestweber D. Corada M. Molendini C. Dejana E. McDonald D.M. Functionally specialized junctions between endothelial cells of lymphatic vessels.J. Exp. Med. 2007; 204: 2349-2362Crossref PubMed Scopus (522) Google Scholar; Muthuchamy and Zawieja, 2008Muthuchamy M. Zawieja D. Molecular regulation of lymphatic contractility.Ann. N Y Acad. Sci. 2008; 1131: 89-99Crossref PubMed Scopus (0) Google Scholar). Collecting lymphatic vessels have valves that regulate the unidirectional flow of lymph (Figure 1). Coordinated contraction of muscle cells facilitates transport of lymph back to the blood circulation (Norrmén et al., 2009Norrmén C. Ivanov K.I. Cheng J. Zangger N. Delorenzi M. Jaquet M. Miura N. Puolakkainen P. Horsley V. Hu J. et al.FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1.J. Cell Biol. 2009; 185: 439-457Crossref PubMed Scopus (202) Google Scholar; Sabine et al., 2016Sabine A. Saygili Demir C. Petrova T.V. Endothelial Cell Responses to Biomechanical Forces in Lymphatic Vessels.Antioxid. Redox Signal. 2016; 25: 451-465Crossref PubMed Scopus (16) Google Scholar). Tissue fluid transported via the collecting lymphatics drains into the thoracic duct and the right lymphatic duct, which, in turn, discharge lymph into the large veins at the base of the neck (Figure 1; Srinivasan and Oliver, 2011Srinivasan R.S. Oliver G. 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The lymphatic system also contains lymph nodes (>200 in humans; Figure 1), whose close integration with the lymphatic vasculature allows the system to initiate and expand immune responses while serving as a filtration barrier that prevents return of noxious stimuli to the blood circulation. With the exception of a brief discussion about lymph nodes in inflammation and immunity, this review focuses mostly on the lymphatic vasculature. Lymphatic vessels have not yet been identified in avascular structures such as the epidermis, hair, nails, and cartilage, nor are they present in some vascularized organs such as the brain and retina. Abnormal lymphatic vasculature invasion into bone has been linked to vanishing bone syndrome (Gorham-Stout disease; Dellinger et al., 2014Dellinger M.T. Garg N. Olsen B.R. Viewpoints on vessels and vanishing bones in Gorham-Stout disease.Bone. 2014; 63: 47-52Crossref PubMed Scopus (77) Google Scholar), although the bone marrow is normally devoid of lymphatic vessels. Major advances have been made in understanding how the lymphatic vasculature develops, particularly in mouse and zebrafish embryos (Geng et al., 2017Geng X. Cha B. Mahamud M.R. Srinivasan R.S. Intraluminal valves: development, function and disease.Dis. Model. Mech. 2017; 10: 1273-1287Crossref PubMed Scopus (13) Google Scholar; Hogan and Schulte-Merker, 2017Hogan B.M. Schulte-Merker S. How to Plumb a Pisces: Understanding Vascular Development and Disease Using Zebrafish Embryos.Dev. Cell. 2017; 42: 567-583Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar; Kazenwadel and Harvey, 2018Kazenwadel J. Harvey N.L. Lymphatic endothelial progenitor cells: origins and roles in lymphangiogenesis.Curr. Opin. 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This knowledge has advanced our understanding of how defects in lymphangiogenesis contribute to human vascular disease.Table 1Genes and Phenotypes Associated with Symptomatic Lymphatic DisordersGeneDisease and PhenotypeReferencesVEGFR3Nonne-Milroy diseaseSeveral heterozygous missense mutations affecting the tyrosine kinase activity of vascular endothelial growth factor receptor 3 (VEGFR3) are responsible for this disease, characterized by congenital bilateral lower limb lymphedema. Mutations in VEGFR3 are also responsible for the mutant mouse strain Chy with defective lymphatic vessels, chylous ascites, and lymphedematous limb swelling after birth.Butler et al., 2007Butler M.G. Dagenais S.L. Rockson S.G. Glover T.W. A novel VEGFR3 mutation causes Milroy disease.Am. J. Med. Genet. A. 2007; 143A: 1212-1217Crossref PubMed Scopus (35) Google Scholar, Butler et al., 2009Butler M.G. Isogai S. Weinstein B.M. Lymphatic development.Birth Defects Res. 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Genet. 2000; 25: 153-159Crossref PubMed Scopus (490) Google ScholarFOXC2Lymphedema-distichiasis (LD) syndromeThis autosomal dominant disorder is characterized by distichiasis (i.e., a double row of eyelashes) at birth and bilateral lower limb lymphedema at puberty. The number of lymphatic vessels appears to be normal in patients with LD; however, they have impaired lymphatic drainage. This defect is likely a consequence of abnormal valve development/function and aberrant mural cell coating in the collecting lymphatic vessels of LD patients and Foxc2 mutant mice. The majority of FOXC2 mutations are insertions, deletions, or nonsense mutations, leading to mRNA decay or truncated loss-of-function proteins.Brice et al., 2002Brice G. Mansour S. Bell R. Collin J.R. Child A.H. Brady A.F. Sarfarazi M. Burnand K.G. Jeffery S. Mortimer P. Murday V.A. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24.J. Med. 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Downes M. et al.Sox18 induces development of the lymphatic vasculature in mice.Nature. 2008; 456: 643-647Crossref PubMed Scopus (333) Google Scholar; Irrthum et al., 2003Irrthum A. Devriendt K. Chitayat D. Matthijs G. Glade C. Steijlen P.M. Fryns J.P. Van Steensel M.A. Vikkula M. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia.Am. J. Hum. Genet. 2003; 72: 1470-1478Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar; Pennisi et al., 2000Pennisi D. Gardner J. Chambers D. Hosking B. Peters J. Muscat G. Abbott C. Koopman P. Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice.Nat. Genet. 2000; 24: 434-437Crossref PubMed Scopus (167) Google ScholarCCBE1Hennekam lymphangiectasia-lymphedema syndrome type 1This syndrome is caused by homozygous and compound heterozygous mutations in the extracellular collagen and calcium-binding epidermal growth factor (EGF) domain-1 protein (CCBE1) and is characterized by severe peripheral lymphedema associated with intestinal lymphangiectasias, characteristic facial features, growth and mental retardation, and hydrops fetalis. CCBE1 is important to facilitate proteolytic cleavage and activation of the major VEGFR3 ligand VEGFC.Alders et al., 2009Alders M. Hogan B.M. Gjini E. Salehi F. Al-Gazali L. Hennekam E.A. Holmberg E.E. Mannens M.M. Mulder M.F. Offerhaus G.J. et al.Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.Nat. Genet. 2009; 41: 1272-1274Crossref PubMed Scopus (178) Google Scholar, Alders et al., 2013Alders M. Mendola A. Adès L. Al Gazali L. Bellini C. Dallapiccola B. Edery P. Frank U. Hornshuh F. 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Rowe P. et al.Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review.Am. J. Med. Genet. 2002; 112: 412-421Crossref PubMed Scopus (77) Google ScholarFAT4Hennekam lymphangiectasia-lymphedema syndrome 2Homozygous and compound heterozygous mutations in FAT4, encoding the giant atypical cadherin FAT4, were identified in Hennekam syndrome patients in whom no CCBE1 mutations were found. FAT4 is important for coordinating LEC polarity in response to flow and, as a result, regulates lymphatic vessel valve development.Alders et al., 2014Alders M. Al-Gazali L. Cordeiro I. Dallapiccola B. Garavelli L. Tuysuz B. Salehi F. Haagmans M.A. Mook O.R. Majoie C.B. et al.Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome.Hum. Genet. 2014; 133: 1161-1167Crossref PubMed Scopus (60) Google Scholar, Betterman et al., 2020Betterman K.L. Sutton D.L. Secker G.A. Kazenwadel J. Oszmiana A. Lim L. Miura N. Sorokin L. Hogan B.M. Kahn M.L. et al.Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow.J. Clin. Invest. 2020; 130: 3315-3328Crossref PubMed Scopus (0) Google Scholar; Pujol et al., 2017Pujol F. Hodgson T. Martinez-Corral I. Prats A.C. Devenport D. Takeichi M. Genot E. Mäkinen T. Francis-West P. Garmy-Susini B. Tatin F. Dachsous1-Fat4 Signaling Controls Endothelial Cell Polarization During Lymphatic Valve Morphogenesis-Brief Report.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 1732-1735Crossref PubMed Scopus (10) Google ScholarADAMTS3Hennekam lymphangiectasia-lymphedema syndrome 3This syndrome is caused by loss of activity of the protease a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3), a protease also required for proteolytic cleavage and activation of VEGFC. In these patients, bi-allelic missense mutations in ADAMTS3 have been identified.Brouillard et al., 2017Brouillard P. Dupont L. Helaers R. Coulie R. Tiller G.E. Peeden J. Colige A. 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Bi W. et al.Biallelic mutation of FBXL7 suggests a novel form of Hennekam syndrome.Am. J. Med. Genet. A. 2020; 182: 189-194Crossref PubMed Scopus (2) Google ScholarGJC2Late-onset autosomal dominant lymphedemaMissense mutations in GJC2 (gap junction protein gamma-2) were discovered in a few families with late-onset autosomal dominant lymphedema affecting all 4 extremities, although some families showed reduced penetrance. GJC2 is a key effector of venous valve development, but the precise role of GJC2 in lymphatic vessels remains enigmatic.Ferrell et al., 2010Ferrell R.E. Baty C.J. Kimak M.A. Karlsson J.M. Lawrence E.C. Franke-Snyder M. Meriney S.D. Feingold E. Finegold D.N. GJC2 missense mutations cause human lymphedema.Am. J. Hum. Genet. 2010; 86: 943-948Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar; Lyons et al., 2017Lyons O. Saha P. Seet C. Kuchta A. Arnold A. Grover S. Rashbrook V. Sabine A. Vizcay-Barrena G. Patel A. et al.Human venous valve disease caused by mutations in FOXC2 and GJC2.J. Exp. Med. 2017; 214: 2437-2452Crossref PubMed Scopus (11) Google Scholar; Ostergaard et al., 2011aOstergaard P. Simpson M.A. Brice G. Mansour S. Connell F.C. Onoufriadis A. Child A.H. Hwang J. Kalidas K. Mortimer P.S. et al.Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.J. Med. Genet. 2011; 48: 251-255Crossref PubMed Scopus (65) Google ScholarGATA2Emberger syndromeHeterozygous loss-of-function mutations in GATA-binding protein 2 have been identified in patients with primary lymphedema with myelodysplasia progressing to acute myeloid leukemia (Emberger syndrome). GATA2 is important for development and maintenance of lymphovenous and lymphatic vessel valves.Geng et al., 2016Geng X. Cha B. Mahamud M.R. Lim K.C. Silasi-Mansat R. Uddin M.K.M. Miura N. Xia L. Simon A.M. 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Gelb B.D. Diaz G.A. Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans.Am. J. Hum. Genet. 2010; 87: 436-444Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarKIF11MCLMRHeterozygous mutations in KIF11 (kinesin family member 11, a DNA-interacting protein encoding the kinesin motor protein EG5) causes MLCRD (microcephaly, lymphedema, and chorioretinal dysplasia) and CDMMR (chorioretinal dysplasia, microcephaly, and mental retardation), 2 allelic syndromes that have now been regrouped as MCLMR (microcephaly with or without chorioretinopathy, lymphedema, or mental retardation). The role of KIF11 in the lymphatic vasculature remains to be established.Ostergaard et al., 2012Ostergaard P. Simpson M.A. Mendola A. Vasudevan P. Connell F.C. van Impel A. Moore A.T. Loeys B.L. Ghalamkarpour A. 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