Voltar
Revisão Acesso aberto Revisado por pares
BIBTEX RIS

New Insights into the Molecular Control of the Lymphatic Vascular System and its Role in Disease

2006; Elsevier BV; Volume: 126; Issue: 10 Linguagem: Inglês

10.1038/sj.jid.5700464

ISSN

1523-1747

Autores

Leah N. Cueni, Michael Detmar,

Tópico(s)

Hippo pathway signaling and YAP/TAZ

Resumo

The cutaneous lymphatic system plays an important role in the maintenance of tissue fluid homeostasis, in the afferent phase of the immune response, and in the metastatic spread of skin cancers. However, the lymphatic system has not received as much scientific attention as the blood vascular system, largely due to a lack of lymphatic-specific markers and to the dearth of knowledge about the molecular regulation of its development and function. The recent identification of genes that specifically control lymphatic development and the growth of lymphatic vessels (lymphangiogenesis), together with the discovery of new lymphatic endothelium-specific markers, have now provided new insights into the molecular mechanisms that control lymphatic growth and function. Moreover, studies of several genetic mouse models have set the framework for a new molecular model for embryonic lymphatic vascular development, and have identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. These scientific advances have also provided surprising evidence that malignant tumors can directly promote lymphangiogenesis and lymphatic metastasis, and that lymphatic vessels play a major role in cutaneous inflammation and in the cutaneous response to UVB irradiation. The cutaneous lymphatic system plays an important role in the maintenance of tissue fluid homeostasis, in the afferent phase of the immune response, and in the metastatic spread of skin cancers. However, the lymphatic system has not received as much scientific attention as the blood vascular system, largely due to a lack of lymphatic-specific markers and to the dearth of knowledge about the molecular regulation of its development and function. The recent identification of genes that specifically control lymphatic development and the growth of lymphatic vessels (lymphangiogenesis), together with the discovery of new lymphatic endothelium-specific markers, have now provided new insights into the molecular mechanisms that control lymphatic growth and function. Moreover, studies of several genetic mouse models have set the framework for a new molecular model for embryonic lymphatic vascular development, and have identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. These scientific advances have also provided surprising evidence that malignant tumors can directly promote lymphangiogenesis and lymphatic metastasis, and that lymphatic vessels play a major role in cutaneous inflammation and in the cutaneous response to UVB irradiation. angiopoietin-1 blood vascular endothelial cell fibroblast growth factor-2 hepatocyte growth factor Kaposi's sarcoma lymphatic endothelial cell vascular endothelial growth factor vascular endothelial growth factor receptor Apart from the cardiovascular system, higher vertebrates also possess a lymphatic system that consists of the lymphatic vessels and the lymphoid organs that include lymph nodes, tonsils, Peyer's patches, spleen, and thymus. Whereas the cardiovascular system forms a closed circle around which blood is pumped by the heart, the lymphatic system comprises a one-way, open-ended network without a central driving force. Lymph, a protein-rich exudate from blood vessels, is taken up by the lymphatic capillaries in the tissue. From there it is returned to the venous circulation via the larger collecting lymphatic vessels and the thoracic duct, which connects the lymphatic system to the inferior vena cava (Figure 1). The pressure gradients to move lymph through the vessels result from skeletal muscle action, respiratory movement, and contraction of smooth muscle cells in vessel walls. The lymphatic system also contributes to the immune surveillance of the body. Lymphatic vessels transport immune cells – including lymphocytes and antigen-presenting dendritic cells – from the skin to regional lymph nodes, where specific immune responses are initiated. In addition, the lacteal lymphatic vessels of the intestine are involved in the uptake of dietary fat and of the fat-soluble vitamins A, D, E, and K from the digestive system. However, recent scientific discoveries have revealed that the lymphatic system also plays a major role in a number of pathologic conditions, including lymphedema, inflammatory diseases, and tumor metastasis. Lymphatic vessels are present in almost all tissues but are absent from avascular structures such as the epidermis, hair, nails, cartilage, and cornea, and from some vascularized organs such as the brain and retina. In the skin, the superficial lymphatic plexus collects lymph from lymphatic capillaries that can extend into the dermal papillae. These lymphatic capillaries are lined by a single, non-fenestrated layer of overlapping endothelial cells, and – in contrast to blood vessels – lack a continuous basement membrane as well as pericyte or smooth muscle cell coverage. Lymphatic endothelial cells (LECs) are connected to the surrounding extracellular matrix by specialized fibrillin-containing anchoring filaments (Gerli et al., 2000Gerli R. Solito R. Weber E. Agliano M. Specific adhesion molecules bind anchoring filaments and endothelial cells in human skin initial lymphatics.Lymphology. 2000; 33: 148-157PubMed Google Scholar). Upon increase of interstitial fluid pressure, these filaments exert tension on LECs, thereby widening the capillary lumen and opening the overlapping cell junctions, which enables the uptake of fluid, macromolecules, and cells. The larger collecting lymphatic vessels in the lower dermis and upper subcutis are surrounded by a basement membrane and by a layer of smooth muscle cells that contribute to lymph propulsion. They contain luminal valves to ensure unidirectional fluid transport. The first description of the lymphatic system dates back to the seventeenth century, when the Italian anatomist Gasparo Aselli identified lymphatic vessels as “milky veins” in the mesentery of a “well-fed” dog (Asellius, 1627Asellius G. De lactibus sive lacteis venis. Mediolani, Milan1627Google Scholar). However, the developmental origin of lymphatic vessels remained unclear until Florence Sabin proposed in 1902 – based upon ink-injection experiments in pigs – that endothelial cells bud off from the veins during early embryonic development and form primitive lymph sacs. The peripheral lymphatic system then originates from these primary lymph sacs by endothelial sprouting into the surrounding tissues and organs, where local capillaries are formed (Sabin, 1902Sabin F.R. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig.Am J Anat. 1902; 1: 367-391Crossref Scopus (349) Google Scholar). This model was challenged in 1910 by Huntington and McClure who alternatively suggested that lymph sacs arise – independently of the veins – from mesenchymal precursor cells (lymphangioblasts), with consecutive establishment of venous connections (Huntington and McClure, 1910Huntington G.S. McClure C.F.W. The anatomy and development of the jugular lymph sac in the domestic cat (Felis domestica).Am J Anat. 1910; 10: 177-311Crossref Scopus (130) Google Scholar). Recent studies in genetically engineered mouse models have now provided clear evidence for the origin of the mammalian lymphatic system from embryonic veins (Oliver, 2004Oliver G. Lymphatic vasculature development.Nat Rev Immunol. 2004; 4: 35-45Crossref PubMed Scopus (303) Google Scholar), and they have also identified some of the molecular determinants that control the step-wise process of lymphatic competence, commitment, differentiation and maturation (Figure 2). Major advances in lymphatic research have been made possible by the recent establishment of defined cultures of blood vascular endothelial cells (BECs) and LECs isolated from human skin (Kriehuber et al., 2001Kriehuber E. Breiteneder-Geleff S. Groeger M. Soleiman A. Schoppmann S.F. Stingl G. et al.Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages.J Exp Med. 2001; 194: 797-808Crossref PubMed Scopus (425) Google Scholar; Makinen et al., 2001Makinen T. Veikkola T. Mustjoki S. Karpanen T. Catimel B. Nice E.C. et al.Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-c/d receptor VEGFR-3.EMBO J. 2001; 20: 4762-4773Crossref PubMed Scopus (631) Google Scholar; Podgrabinska et al., 2002Podgrabinska S. Braun P. Velasco P. Kloos B. Pepper M.S. Skobe M. Molecular characterization of lymphatic endothelial cells.Proc Natl Acad Sci USA. 2002; 99: 16069-16074Crossref PubMed Scopus (366) Google Scholar; Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar). These cells maintain their lineage-specific differentiation even after several passages in vitro. Comparative microarray analyses of their specific transcriptomes revealed that the majority of all genes investigated (appr. 98%) were expressed at comparable levels by the two endothelial cell types (Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar; Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar), corroborating their close genetic relationship. However, these studies have also identified numerous, previously unknown lineage-specific markers for blood vascular and lymphatic endothelium (Table 1). Whereas the specific function of the majority of the differentially expressed genes still remains unknown, the study of several lymphatic-specific molecules has provided important new insights into the molecular control of lymphatic development and function (Table 2).Table 1Specific markers for LV versus BVMarkersFunctionLVBVReferencesProx1Transcription factor++−(Wigle and Oliver, 1999Wigle J.T. Oliver G. Prox1 function is required for the development of the murine lymphatic system.Cell. 1999; 98: 769-778Abstract Full Text Full Text PDF PubMed Scopus (1141) Google Scholar)PodoplaninTransmembrane glycoprotein++−(Wetterwald et al., 1996Wetterwald A. Hoffstetter W. Cecchini M.G. Lanske B. Wagner C. Fleisch H. et al.Characterization and cloning of the e11 antigen, a marker expressed by rat osteoblasts and osteocytes.Bone. 1996; 18: 125-132Abstract Full Text PDF PubMed Scopus (239) Google Scholar; Breiteneder-Geleff et al., 1999Breiteneder-Geleff S. Soleiman A. Kowalski H. Horvat R. Amann G. Kriehvber E. et al.Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: Podoplanin as a specific marker for lymphatic endothelium.Am J Pathol. 1999; 154: 385-394Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar)LYVE-1Hyaluronan receptor++−(Banerji et al., 1999Banerji S. Ni J. Wang S.X. Clasper S. Su J. Tammi R. et al.LYVE-1, a new homologue of the cd44 glycoprotein, is a lymph-specific receptor for hyaluronan.J Cell Biol. 1999; 144: 789-801Crossref PubMed Scopus (1214) Google Scholar)VEGFR-3Growth factor receptor+−/(+)1VEGFR-3 expression was also found on some blood capillaries during tumor neovascularization and in wound granulation tissue (Valtola et al., 1999; Paavonen et al., 2000).(Kaipainen et al., 1995Kaipainen A. Korhonen J. Mustonen T. van Hinsbergh V.W. Fang G.H. Dumont D. et al.Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development.Proc Natl Acad Sci USA. 1995; 92: 3566-3570Crossref PubMed Scopus (1139) Google Scholar)Neuropilin-2Semaphorin and growth factor receptor+−/(+)2Neuropilin-2 is also expressed in veins (Yuan et al., 2002).(Yuan et al., 2002Yuan L. Moyon D. Pardanaud L. Breant C. Karkkainen M.J. Alitalo K. et al.Abnormal lymphatic vessel development in neuropilin 2 mutant mice.Development. 2002; 129: 4797-4806Crossref PubMed Google Scholar)Macrophage mannose receptor 1L-selectin receptor+−(Irjala et al., 2001Irjala H. Johansson E.L. Grenman R. Alanen K. Salmi M. Jalkanen S. et al.Mannose receptor is a novel ligand for l-selectin and mediates lymphocyte binding to lymphatic endothelium.J Exp Med. 2001; 194: 1033-1042Crossref PubMed Scopus (129) Google Scholar)CCL21CC-chemokine+−(Gunn et al., 1998Gunn M.D. Tangemann K. Tam C. Cyster J.G. Rosen S.D. Williams L.T. et al.A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes.Proc Natl Acad Sci USA. 1998; 95: 258-263Crossref PubMed Scopus (836) Google Scholar)CCL20CC-chemokine+ (++)3After activation, both blood vascular and lymphatic endothelial cells strongly express CCL20 (Kriehuber et al., 2001).− (++)3After activation, both blood vascular and lymphatic endothelial cells strongly express CCL20 (Kriehuber et al., 2001).(Kriehuber et al., 2001Kriehuber E. Breiteneder-Geleff S. Groeger M. Soleiman A. Schoppmann S.F. Stingl G. et al.Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages.J Exp Med. 2001; 194: 797-808Crossref PubMed Scopus (425) Google Scholar; Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)DesmoplakinAnchoring protein of adhering junctions+−(Ebata et al., 2001Ebata N. Nodasaka Y. Sawa Y. Yamaoka Y. Makino S. Totsuka Y. et al.Desmoplakin as a specific marker of lymphatic vessels.Microvasc Res. 2001; 61: 40-48Crossref PubMed Scopus (61) Google Scholar)PlakoglobinConnect cadherins to cytoskeleton in cell–cell junctions+−(Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar; Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)Integrin α9Adhesion molecule, subunit of osteopontin and tenascin receptors, VEGFR-3 coreceptor?+−(Huang et al., 2000Huang X.Z. Wu J.F. Ferrando R. Lee J.H. Wang Y.L. Farese R.V. et al.Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1.Mol Cell Biol. 2000; 20: 5208-5215Crossref PubMed Scopus (246) Google Scholar; Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar)CD44Hyaluronan receptor−+(Kriehuber et al., 2001Kriehuber E. Breiteneder-Geleff S. Groeger M. Soleiman A. Schoppmann S.F. Stingl G. et al.Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages.J Exp Med. 2001; 194: 797-808Crossref PubMed Scopus (425) Google Scholar)VEGF-CGrowth factor−+(Kriehuber et al., 2001Kriehuber E. Breiteneder-Geleff S. Groeger M. Soleiman A. Schoppmann S.F. Stingl G. et al.Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages.J Exp Med. 2001; 194: 797-808Crossref PubMed Scopus (425) Google Scholar; Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)VEGFR-1Growth factor receptor−+(Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)Neuropilin-1Semaphorin and growth factor receptor−+(Hong et al., 2002Hong Y.K. Harvey N. Noh Y.H. Schacht V. Hirakawa S. Detmar M. et al.Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate.Dev Dyn. 2002; 225: 351-357Crossref PubMed Scopus (397) Google Scholar; Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar)Endoglin/CD105Low-affinity receptor for TGF-β−++(Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)CD34L-selectin receptor−/(+)4CD34 expression has also been found on lymphatic endothelial cells (Sauter et al., 1998; Kriehuber et al., 2001).++(Young et al., 1995Young P.E. Baumhueter S. Lasky L.A. The sialomucin cd34 is expressed on hematopoietic cells and blood vessels during murine development.Blood. 1995; 85: 96-105PubMed Google Scholar)IL-8CXC-chemokine−+(Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar)N-cadherinAdhesion molecule−+(Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar; Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)ICAM-1/CD54Adhesion molecule−+(Erhard et al., 1996Erhard H. Rietveld F.J. Brocker E.B. de Waal R.M. Ruiter D.J. Phenotype of normal cutaneous microvasculature. Immunoelectron microscopic observations with emphasis on the differences between blood vessels and lymphatics.J Invest Dermatol. 1996; 106: 135-140Crossref PubMed Scopus (54) Google Scholar)Integrin α5Adhesion molecule, subunit of fibronectin receptor−+(Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar; Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)Collagen IVExtracellular matrix protein−/(+)5Peripheral lymphatic vessels sometimes have an incomplete basement membrane, large collecting vessels a complete one.++(Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)VersicanChondroitin sulfate proteoglycan−+(Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar; Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)LamininBasement membrane molecule−/(+)5Peripheral lymphatic vessels sometimes have an incomplete basement membrane, large collecting vessels a complete one.++(Barsky et al., 1983Barsky S.H. Baker A. Siegal G.P. Togo S. Liotta L.A. Use of anti-basement membrane antibodies to distinguish blood vessel capillaries from lymphatic capillaries.Am J Surg Pathol. 1983; 7: 667-677Crossref PubMed Scopus (115) Google Scholar; Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar)Collagen XVIIIBasement membrane molecule−/(+)5Peripheral lymphatic vessels sometimes have an incomplete basement membrane, large collecting vessels a complete one.++(Petrova et al., 2002Petrova T.V. Makinen T. Makela T.P. Saarela J. Virtanen I. Ferrell R.E. et al.Lymphatic endothelial reprogramming of vascular endothelial cells by the prox-1 homeobox transcription factor.EMBO J. 2002; 21: 4593-4599Crossref PubMed Scopus (506) Google Scholar; Hirakawa et al., 2003Hirakawa S. Hong Y.K. Harvey N. Schacht V. Matsuda K. Libermann T. et al.Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.Am J Pathol. 2003; 162: 575-586Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar)PAL-ECaveolae-associated glycoprotein?−++(Schlingemann et al., 1985Schlingemann R.O. Dingjan G.M. Emeis J.J. Blok J. Warnaar S.O. Ruiter D.J. et al.Monoclonal antibody pal-e specific for endothelium.Lab Invest. 1985; 52: 71-76PubMed Google Scholar; Niemela et al., 2005Niemela H. Elima K. Henttinen T. Irjala H. Salmi M. Jalkanen S. et al.Molecular identification of pal-e, a widely used endothelial-cell marker.Blood. 2005; 106: 3405-3409Crossref PubMed Scopus (54) Google Scholar)BV, blood vessel; CCL, CC chemokine ligand; LV, lymphatic vessel; LYVE-1, lymphatic vascular endothelial hyaluronan receptor-1; PAL-E, pathologische anatomie leiden-endothelium; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.1 VEGFR-3 expression was also found on some blood capillaries during tumor neovascularization and in wound granulation tissue (Valtola et al., 1999Valtola R. Salven P. Heikkila P. Taipale J. Joensuu H. Rehn M. et al.VEGFR-3 and its ligand VEGF-c are associated with angiogenesis in breast cancer.Am J Pathol. 1999; 154: 1381-1390Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar; Paavonen et al., 2000Paavonen K. Puolakkainen P. Jussila L. Jahkola T. Alitalo K. Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing.Am J Pathol. 2000; 156: 1499-1504Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar).2 Neuropilin-2 is also expressed in veins (Yuan et al., 2002Yuan L. Moyon D. Pardanaud L. Breant C. Karkkainen M.J. Alitalo K. et al.Abnormal lymphatic vessel development in neuropilin 2 mutant mice.Development. 2002; 129: 4797-4806Crossref PubMed Google Scholar).3 After activation, both blood vascular and lymphatic endothelial cells strongly express CCL20 (Kriehuber et al., 2001Kriehuber E. Breiteneder-Geleff S. Groeger M. Soleiman A. Schoppmann S.F. Stingl G. et al.Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages.J Exp Med. 2001; 194: 797-808Crossref PubMed Scopus (425) Google Scholar).4 CD34 expression has also been found on lymphatic endothelial cells (Sauter et al., 1998Sauter B. Foedinger D. Sterniczky B. Wolff K. Rappersberger K. Immunoelectron microscopic characterization of human dermal lymphatic microvascular endothelial cells. Differential expression of cd31, cd34, and type iv collagen with lymphatic endothelial cells vs blood capillary endothelial cells in normal human skin, lymphangioma, and hemangioma in situ.J Histochem Cytochem. 1998; 46: 165-176Crossref PubMed Scopus (138) Google Scholar; Kriehuber et al., 2001Kriehuber E. Breiteneder-Geleff S. Groeger M. Soleiman A. Schoppmann S.F. Stingl G. et al.Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages.J Exp Med. 2001; 194: 797-808Crossref PubMed Scopus (425) Google Scholar).5 Peripheral lymphatic vessels sometimes have an incomplete basement membrane, large collecting vessels a complete one. Open table in a new tab Table 2Genetic mouse models with abnormalities of the lymphatic systemGenesFunctionModelsPhenotypeReferencesIntegrin α9Adhesion receptorKORespiratory failure caused by pleural fluid (chylothorax), lymphedema(Huang et al., 2000Huang X.Z. Wu J.F. Ferrando R. Lee J.H. Wang Y.L. Farese R.V. et al.Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1.Mol Cell Biol. 2000; 20: 5208-5215Crossref PubMed Scopus (246) Google Scholar)Angiopoietin-1Growth factorTGHyperplastic lymphatic vessels(Tammela et al., 2005Tammela T. Saaristo A. Lohela M. Morisada T. Tornberg J. Norrmen C. et al.Angiopoietin-1 promotes lymphatic sprouting and hyperplasia.Blood. 2005; 105: 4642-4648Crossref PubMed Scopus (195) Google Scholar)Angiopoietin-2Growth factorKOChylous ascites and peripheral edema, abnormal patterning of lymphatic vasculature(Gale et al., 2002Gale N.W. Thurston G. Hackett S.F. Renard R. Wang Q. McClain J. et al.Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1.Dev Cell. 2002; 3: 411-423Abstract Full Text Full Text PDF PubMed Scopus (771) Google Scholar)VEGF-CGrowth factorTGHyperplastic lymphatic vessels(Jeltsch et al., 1997Jeltsch M. Kaipainen A. Joukov V. Meng X. Lakso M. Rauvala H. et al.Hyperplasia of lymphatic vessels in VEGF-c transgenic mice.Science. 1997; 276: 1423-1425Crossref PubMed Scopus (1062) Google Scholar)VEGF-CGrowth factorKONo lymphatic vasculature (−/−), delayed lymphatic vascular development, lymphatic hypoplasia and lymphedema (+/−)(Karkkainen et al., 2004Karkkainen M.J. Haiko P. Sainio K. Partanen J. Taipale J. Petrova T.V. et al.Vascular endothelial growth factor c is required for sprouting of the first lymphatic vessels from embryonic veins.Nat Immunol. 2004; 5: 74-80Crossref PubMed Scopus (974) Google Scholar)HGFGrowth factorTGEnhanced formation and enlargement of lymphatic vessels(Kajiya et al., 2005Kajiya K. Hirakawa S. Ma B. Drinnenberg I. Detmar M. Hepatocyte growth factor promotes lymphatic vessel formation and function.EMBO J. 2005; 24: 2885-2895Crossref PubMed Scopus (246) Google Scholar)VEGFR-3Growth factor receptorKOCardiovascular failure, defective remodelling of vascular networks(Dumont et al., 1998Dumont D.J. Jussila L. Taipale J. Lymboussaki A. Mustonen T. Pajusula K. et al.Cardiovascular failure in mouse embryos deficient in VEGF receptor-3.Science. 1998; 282: 946-949Crossref PubMed Scopus (664) Google Scholar)VEGFR-3Growth factor receptorChy mice (inactivating mutation)Lymphedema(Karkkainen et al., 2001Karkkainen M.J. Saaristo A. Jussila L. Karila K.A. Lawrence E.C. Pajusola K. et al.A model for gene therapy of human hereditary lymphedema.Proc Natl Acad Sci USA. 2001; 98: 12677-12682Crossref PubMed Scopus (457) Google Scholar)Neuropilin-2Growth factor receptorKOAbsence or severe reduction of small lymphatic vessels and capillaries during development(Yuan et al., 2002Yuan L. Moyon D. Pardanaud L. Breant C. Karkkainen M.J. Alitalo K. et al.Abnormal lymphatic vessel development in neuropilin 2 mutant mice.Development. 2002; 129: 4797-4806Crossref PubMed Google Scholar)Prox1Transcription factorKONo lymphatic vasculature (−/−), adult-onset obesity, chylous ascites (+/−)(Wigle and Oliver, 1999Wigle J.T. Oliver G. Prox1 function is required for the development of the murine lymphatic system.Cell. 1999; 98: 769-778Abstract Full Text Full Text PDF PubMed Scopus (1141) Google Scholar; Harvey et al., 2005Harvey N.L. Srinivasan R.S. Dillard M.E. Johnson N.C. Witte M.H. Boyd K. et al.Lymphatic vascular defects promoted by prox1 haploinsufficiency cause adult-onset obesity.Nat Genet. 2005; 37: 1072-1081Crossref PubMed Scopus (377) Google Scholar)FOXC2Transcription factorKOLymphatic hyperplasia (+/−), abnormal patterning and pericyte investment of lymphatic vessels, agenesis of valves, lym

Referência(s)