Abstract
Featured Article
Lymph hearts are pulsatile organs, present in lower vertebrates, that function to propel lymph into the venous system. Although they are absent in mammals, the initial veno-lymphatic plexus that forms during mammalian jugular lymph sac development has been described as the vestigial homologue of the nascent stage of ancestral anterior lymph hearts. Despite the widespread presence of lymph hearts among vertebrate species and their unique function, extremely little is known about lymph heart development. We show that Xenopus anterior lymph heart muscle expresses skeletal muscle markers such as myoD and 12/101, rather than cardiac markers. The onset of lymph heart myoblast induction can be visualized by engrailed-1 (en1) staining in anterior trunk somites, which is dependent on Hedgehog (Hh) signaling. In the absence of Hh signaling and upon en1 knockdown, lymph heart muscle fails to develop, despite the normal development of the lymphatic endothelium of the lymph heart, and embryos develop edema. These results suggest a mechanism for the evolutionary transition from anterior lymph hearts to jugular lymph sacs in mammals.
Discussion
Peyrot and colleagues explore the embryology of “lymph hearts”, which are juxtaposed between the lymphatic and venous systems of lower vertebrates such as frogs. Mammals lack a lymph heart, however, evidence suggests that early mammalian jugular lymph sac formation resembles this structure.
There are three layers comprising the lymph heart—an endothelial cell lining (controlled by Homeobox prospero-like protein PROX1), skeletal muscle, and outer fibroelastic layer. The authors study the mechanisms controlling lymph heart myoblastogenesis, demonstrating the specific requirement of the Homeobox protein engrailed-1 (en-1 of the Hedgehog pathway) in lymph heart muscle development.
Xenopus laevis (African clawed frog) embryos were studied. Inhibition of the hedgehog pathway by Cyclopamine, a hedgehog gene (Hh) suppressor, inhibited en-1 expression and led to lack of en-1-expressing myoblasts and lymph heart muscle. Prox-1 positive tissues were unaffected, and the animals (embryos) developed edema, showing that lymph heart musculature is required for its function. Functional inhibition of lymph heart musculature with benzocaine also resulted in edema. The results of elegant experiments are represented by immunohistochemistry.
They conclude that the lack of lymph hearts in higher vertebrates may relate to modifications of signaling pathways modulating lymph heart myogenesis.
Basic Science
Alders, M., B. M. Hogan, et al. (2009). “Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.” Nat Genet
Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome. Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish. Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans.
Attout, T., A. Hoerauf, et al. (2009). “Lymphatic vascularisation and involvement of lyve-1 macrophages in the human onchocerca nodule.” PLoS One
Cimpean, A. M., E. Seclaman, et al. (2009). “VEGF-A/HGF induce Prox-1 expression in the chick embryo chorioallantoic membrane lymphatic vasculature.” Clin Exp Med. Dec 24. [Epub ahead of print].
Vascular endothelial growth factor-A (VEGF-A) and hepatocyte growth factor (HGF) are well known angiogenesis inductors and promoters in normal and pathologic conditions. Recent data showed that VEGF-A and HGF could also influence lymphangiogenesis but this matter has not been completely elucidated. Administration of VEGF-A and HGF in combination has been used to improve the angiogenic response in different experimental models, but their effects on lymphangiogenesis have not been investigated. The aim of this study was to characterize blood and lymphatic vascular response to VEGF-A/HGF administration. To this purpose, we built a pBlast VEGF-A/HGF combination suitable for in vivo research. By using as an experimental in vivo model the chick embryo chorioallantoic membrane (CAM) assay, we applied pBlast VEGF-A/HGF combination for 7 days. Results showed that VEGF-A/HGF combination was able to induce a strong angiogenic response and the expression of Prox-1 in the lymphatic endothelial cells of the CAM. The possible mechanisms involved have been speculated.
Connell, F., K. Kalidas, et al. (2010). “Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia.” Hum Genet
Generalised lymphatic dysplasia (GLD) is characterised by extensive peripheral lymphoedema with visceral involvement. In some cases, it presents in utero with hydrops fetalis. Autosomal dominant and recessive inheritance has been reported. A large, non-consanguineous family with three affected siblings with generalised lymphatic dysplasia is presented. One child died aged 5 months, one spontaneously miscarried at 17 weeks gestation, and the third has survived with extensive lymphoedema. All three presented with hydrops fetalis. There are seven other siblings who are clinically unaffected. Linkage analysis produced two loci on chromosome 18, covering 22 Mb and containing 150 genes, one of which is CCBE1. A homozygous cysteine to serine change in CCBE1 has been identified in the proband, in a residue that is conserved across species. High density SNP analysis revealed homozygosity (a region of 900 kb) around the locus for CCBE1 in all three affected cases. This indicates a likely ancestral mutation that is common to both parents; an example of a homozygous mutation representing Identity by Descent (IBD) in this pedigree. Recent studies in zebrafish have shown this gene to be required for lymphangiogenesis and venous sprouting and are therefore supportive of our findings. In view of the conserved nature of the cysteine, the nature of the amino acid change, the occurrence of a homozygous region around the locus, the segregation within the family, and the evidence from zebrafish, we propose that this mutation is causative for the generalised lymphatic dysplasia in this family, and may be of relevance in cases of non-immune hydrops fetalis.
Cosson, E., F. Cohen-Boulakia, et al. (2009). “Capillary endothelial but not lymphatic function is restored under rosiglitazone in Zucker diabetic fatty rats.” Microvasc Res
Cui, Y. (2010). “Impact of lymphatic vessels on the heart.” Thorac Cardiovasc Surg
D'Amico, G., D. T. Jones, et al. (2009). “Regulation of lymphatic-blood vessel separation by endothelial Rac1.” Development
Sprouting angiogenesis and lymphatic-blood vessel segregation both involve the migration of endothelial cells, but the precise migratory molecules that govern the decision of blood vascular endothelial cells to segregate into lymphatic vasculature are unknown. Here, we deleted endothelial Rac1 in mice (Tie1-Cre(+);Rac1(fl/fl)) and revealed, unexpectedly, that whereas blood vessel morphology appeared normal, lymphatic-blood vessel separation was impaired, with corresponding edema, haemorrhage and embryonic lethality. Importantly, normal levels of Rac1 were essential for directed endothelial cell migratory responses to lymphatic-inductive signals. Our studies identify Rac1 as a crucial part of the migratory machinery required for endothelial cells to separate and form lymphatic vasculature.
Ebisuno, Y., K. Katagiri, et al. (2009). “Rap1 controls lymphocyte adhesion cascades and interstitial migration within lymph nodes in RAPL-dependent and -independent manners.” Blood.
The small GTPase Rap1 and its effector RAPL regulate lymphocyte adhesion and motility. However, their precise regulatory roles in the adhesion cascade preceding entry into lymph nodes and during interstitial migration are unclear. Here, we show that Rap1 is indispensably required for the chemokine-triggered initial arrest step of rolling lymphocytes through LFA-1, whereas RAPL is not involved in rapid arrest. RAPL and talin play a critical role in stabilizing lymphocyte arrest to the endothelium of blood vessels under flow or to the high endothelial venules of peripheral lymph nodes in vivo. Further, mutagenesis and peptide studies suggest that release of a trans-acting restraint from the beta2 cytoplasmic region of LFA-1 is critical for Rap1-dependent initial arrest. Rap1 or RAPL deficiency severely impaired lymphocyte motility over lymph node stromal cells in vitro, and RAPL deficiency impaired high-velocity directional movement within lymph nodes. These findings reveal the several critical steps of Rap1, which are RAPL-dependent and -independent, in lymphocyte trafficking.
Fang, J. F., L. Y. Shih, et al. (2009). “Proteomic Analysis of Post-hemorrhagic Shock Mesenteric Lymph.” Shock. Dec 15. [Epub ahead of print].
Fukumoto, A., K. Maruyama, et al. (2009). “Intracellular Thiol Redox Status Regulates Lymphatic Vessel Growth in the Cornea and Dictates Corneal Limbal Graft Survival.” Invest Ophthalmol Vis Sci. Dec 30. [Epub ahead of print].
Hamada, T., Y. Kodama, et al. (2009). “Missense Mutation of Abcg5 in Stroke-Prone Spontaneously Hypertensive Rats Does Not Influence Lymphatic Sitosterol Absorption Regardless of the Dose: Comparison with Wistar Rats.” Biosci Biotechnol Biochem.
Henno, A., S. Blacher, et al. (2010). “Histological and transcriptional study of angiogenesis and lymphangiogenesis in uninvolved skin, acute pinpoint lesions and established psoriasis plaques: An approach of vascular development chronology in psoriasis.” J Dermatol Sci.
Hugon, J., L. Barthelemy, et al. (2009). “The pathway to drive decompression microbubbles from the tissues to the blood and the lymphatic system as a part of this transfer.” Undersea Hyperb Med
Iriyama, S., Y. Matsunaga, et al. (2010). “Heparanase activation induces epidermal hyperplasia, angiogenesis, lymphangiogenesis and wrinkles.” Exp Dermatol. Jan 22. [Epub ahead of print].
Please cite this paper as: Heparanase activation induces epidermal hyperplasia, angiogenesis, lymphangiogenesis and wrinkles. Experimental Dermatology 2010. Abstract: To clarify the difference between cutaneous responses to single and repeated barrier disruption, changes of epidermal gene expression were examined by using RT-PCR. In repeatedly barrier-disrupted skin, heparanase was specifically up-regulated in epidermis. In addition, there was a marked decrease in heparan sulfate (HS) chains of perlecan in basement membrane at the dermal-epidermal junction (DEJ) compared with singly disrupted skin. HS chains form a reservoir for heparan sulfate-binding growth factors. In repeatedly barrier-disrupted skin, expression of vascular endothelial growth factor-A (VEGF-A), an angiogenic factor, was induced in epidermis, whereas thrombospondin-1 (TSP-1), an angiogenesis inhibitor, was down-regulated, and concomitantly blood vessels were elongated and enlarged in dermis. Expression of VEGF-C, a lymphangiogenesis factor, was augmented in epidermis of repeatedly barrier-disrupted skin, concomitantly with an increase in the number and size of lymphatic vessels. Topical application of a synthetic heparanase inhibitor, 1-[4-(1H-benzoimidazol-2-yl)phenyl]-3-[4-(1H-benzoimidazol-2-yl)phenyl]ure a, to skin after barrier disruption significantly suppressed wrinkle formation, degradation of HS chains in the basement membrane, epidermal hyperplasia and the changes of blood and lymphatic vessels. These results suggest that chronic barrier disruption activates heparanase and induces gene expression changes, leading to increased growth factor interaction between epidermis and dermis, and facilitating various cutaneous changes, including wrinkle formation.
LeClair, E. E. and J. Topczewski (2010). “Development and regeneration of the zebrafish maxillary barbel: a novel study system for vertebrate tissue growth and repair.” PLoS One
Leppanen, V. M., A. E. Prota, et al. (2010). “Structural determinants of growth factor binding and specificity by VEGF receptor 2.” Proc Natl Acad Sci U S A
Liu, R., X. Li, et al. (2009). “KSHV induced notch components render endothelial and mural cell characteristics and cell survival.” Blood.
Milling, S. and G. MacPherson (2010). “Isolation of rat intestinal lymph DC.” Methods Mol Biol
Miteva, D. O., J. M. Rutkowski, et al. (2010). “Transmural Flow Modulates Cell and Fluid Transport Functions of Lymphatic Endothelium.” Circ Res. Feb 4. [Epub ahead of print].
Rationale: Lymphatic transport of peripheral interstitial fluid and dendritic cells (DCs) is important for both adaptive immunity and maintenance of tolerance to self-antigens. Lymphatic drainage can change rapidly and dramatically on tissue injury or inflammation, and therefore increased fluid flow may serve as an important early cue for inflammation; however, the effects of transmural flow on lymphatic function are unknown. Objective: Here we tested the hypothesis that lymph drainage regulates the fluid and cell transport functions of lymphatic endothelium. Methods and Results: Using in vitro and in vivo models, we demonstrated that lymphatic endothelium is sensitive to low levels of transmural flow. Basal-to-luminal flow (0.1 and 1 mum/sec) increased lymphatic permeability, dextran transport, and aquaporin-2 expression, as well as DC transmigration into lymphatics. The latter was associated with increased lymphatic expression of the DC homing chemokine CCL21 and the adhesion molecules intercellular adhesion molecule-1 and endothelial selectin. In addition, transmural flow induced delocalization and downregulation of vascular endothelial cadherin and PECAM-1 (platelet/endothelial cell adhesion molecule-1). Flow-enhanced DC transmigration could be reversed by blocking CCR7, intercellular adhesion molecule-1, or endothelial selectin. In an experimental model of lymphedema, where lymphatic drainage is greatly reduced or absent, lymphatic endothelial expression of CCL21 was nearly absent. Conclusions: These findings introduce transmural flow as an important regulator of lymphatic endothelial function and suggest that flow might serve as an early inflammatory signal for lymphatics, causing them to regulate transport functions to facilitate the delivery of soluble antigens and DCs to lymph nodes.
Nagra, G., M. Wagshul, et al. (2010). “Elevated CSF outflow resistance associated with impaired lymphatic CSF absorption in a rat model of kaolin-induced communicating hydrocephalus.” Cerebrospinal Fluid Research
Nakamura, K., K. Radhakrishnan, et al. (2009). “Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice.” PLoS One
BACKGROUND: Disruption of the lymphatic vasculature causes edema, inflammation, and end-tissue destruction. To assess the therapeutic efficacy of systemic anti-inflammatory therapy in this disease, we examined the impact of a nonsteroidal anti-inflammatory drug (NSAID), ketoprofen, and of a soluble TNF-alpha receptor (sTNF-R1) upon tumor necrosis factor (TNF)-alpha activity in a mouse model of acquired lymphedema. METHODS AND FINDINGS: Lymphedema was induced by microsurgical ablation of major lymphatic conduits in the murine tail. Untreated control mice with lymphedema developed significant edema and extensive histopathological inflammation compared to sham surgical controls. Short-term ketoprofen treatment reduced tail edema and normalized the histopathology while paradoxically increasing TNF-alpha gene expression and cytokine levels. Conversely, sTNF-R1 treatment increased tail volume, exacerbated the histopathology, and decreased TNF-alpha gene expression. Expression of vascular endothelial growth factor-C (VEGF-C), which stimulates lymphangiogenesis, closely correlated with TNF-alpha expression. CONCLUSIONS: Ketoprofen therapy reduces experimental post-surgical lymphedema, yet direct TNF-alpha inhibition does not. Reducing inflammation while preserving TNF-alpha activity appears to optimize the repair response. It is possible that the observed favorable responses, at least in part, are mediated through enhanced VEGF-C signaling.
Neusser, M. A., A. K. Kraus, et al. (2010). “The chemokine receptor CXCR7 is expressed on lymphatic endothelial cells during renal allograft rejection.” Kidney Int. Feb 17. [Epub ahead of print].
CXCR7 is an atypical receptor for the chemokines CXCL11 and CXCL12, which were found to be involved in animal models of allograft injury. We studied the expression of CXCR7 and its ligands in human kidneys by first quantifying the mRNA in 53 renal allograft biopsies. Receptor and ligand mRNAs were expressed in renal allografts, with a significant induction of CXCL11 and CXCL12 in biopsies showing borderline lesions and acute rejection. Immunohistochemical analysis for CXCR7 was performed in a series of 64 indication and 24 protocol biopsies. The indication biopsies included 46 acute rejections, 6 with interstitial fibrosis and tubular atrophy, and 12 pretransplant biopsies as controls. In control biopsies, CXCR7 protein was found on smooth muscle and on endothelial cells of a small number of peritubular vessels. The number of CXCR7-positive vessels was increased in acute rejection and, using double immunofluorescence labeling, a subset of these CXCR7-positive endothelial cells were identified as lymphatic vessels. Both CXCR7-positive blood and lymphatic vessels increased during allograft rejection. We found that CXCR7 is present in both blood and lymphatic endothelial cells in human renal allografts. Whether its presence modulates the formation of chemokine gradients and the recruitment of inflammatory cells will require further experimental studies.Kidney International advance online publication, 17 February 2010; doi:10.1038/ki.2010.6.
Norrmen, C., W. Vandevelde, et al. (2009). “Liprin {beta}1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity.” Blood.
The lymphatic vasculature is important for the regulation of tissue fluid homeostasis, immune response and lipid absorption, and the development of in vitro models should allow for better understanding of the mechanisms regulating lymphatic vascular growth, repair and function. Here we report isolation and characterization of lymphatic endothelial cells from human intestine and show that intestinal lymphatic endothelial cells have a related but distinct gene expression profile from human dermal lymphatic endothelial cells. We furthermore identify liprin beta1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, as highly expressed in intestinal lymphatic endothelial cells in vitro and lymphatic vasculature in vivo, and show that it plays an important role in the maintenance of lymphatic vessel integrity in Xenopus tadpoles.
O'Mahony, S., T. B. Britton, et al. (2009). “Delivery of radiolabelled blood cells to lymphatic vessels by intradermal injection: a means of investigating lymphovenous communications in the upper limb.” Nucl Med Commun.
Oliver, G. and R. S. Srinivasan (2010). “Endothelial cell plasticity: how to become and remain a lymphatic endothelial cell.” Development
Lineage commitment and differentiation into mature cell types are mostly considered to be unidirectional and irreversible processes. However, recent results have challenged this by showing that terminally differentiated cell types can be reprogrammed into other cell types, an important step towards devising strategies for gene therapy and tissue regeneration. In this Review, we summarize recent data on the earliest steps in the development of the mammalian lymphatic vasculature: the specification of lymphatic endothelial cells (LECs). We elaborate on a developmental model that integrates the different steps leading to LEC differentiation and lymphatic network formation, discuss evidence that suggests that LEC fate is plastic, and consider the potentially far-reaching implications of the ability to convert one cell type into another.
Pflicke, H. and M. Sixt (2009). “Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels.” J Exp Med.
Pham, T. H., P. Baluk, et al. (2009). “Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning.” J Exp Med.
Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P is not defined. We generated mice that expressed Cre from the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and that showed efficient recombination of loxP-flanked genes in lymphatic endothelium. We report that mice with Lyve-1 CRE-mediated ablation of sphingosine kinase (Sphk) 1 and lacking Sphk2 have a loss of S1P in lymph while maintaining normal plasma S1P. In Lyve-1 Cre(+) Sphk-deficient mice, lymphocyte egress from LNs and Peyer's patches is blocked. Treatment with pertussis toxin to overcome Galphai-mediated retention signals restores lymphocyte egress. Furthermore, in the absence of lymphatic Sphks, the initial lymphatic vessels in nonlymphoid tissues show an irregular morphology and a less organized vascular endothelial cadherin distribution at cell-cell junctions. Our data provide evidence that lymphatic endothelial cells are an in vivo source of S1P required for lymphocyte egress from LNs and Peyer's patches, and suggest a role for S1P in lymphatic vessel maturation.
Reynolds, H. M., C. G. Walker, et al. (2010). “Functional anatomy of the lymphatics draining the skin: a detailed statistical analysis.” J Anat. Jan 7. [Epub ahead of print].
Rienstra, H., K. Katta, et al. (2010). “Differential Expression of Proteoglycans in Tissue Remodeling and Lymphangiogenesis after Experimental Renal Transplantation in Rats.” PLoS One
Rossi, A., F. Sozio, et al. (2009). “Lymphatic and blood vessels in scleroderma skin, a morphometric analysis.” Hum Pathol. ;
Rutkowski, J. M., C. E. Markhus, et al. (2010). “Dermal Collagen and Lipid Deposition Correlate with Tissue Swelling and Hydraulic Conductivity in Murine Primary Lymphedema.” Am J Pathol. Jan 28. [Epub ahead of print]
Scallan, J. P. and V. H. Huxley (2010). “In vivo determination of collecting lymphatic vessel permeability to albumin: a role for lymphatics in exchange.” J Physiol
Schonthaler, H. B., R. Huggenberger, et al. (2009). “Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis.” Proc Natl Acad Sci U S A.
Shibata, H., A. Okazaki, et al. (2009). “Patterns of efferent lymphatics of the rabbit testis.” J Vet Med Sci
Soong, T. R., A. P. Pathak, et al. (2010). “Lymphatic Injury and Regeneration in Cardiac Allografts.” Transplantation. Jan 28. [Epub ahead of print].
BACKGROUND.: Severed donor heart lymphatics are not anastomosed to recipient lymphatics in cardiac transplantation. We evaluated the effects of cellular infiltrates of T cells and macrophages on the morphology of lymphatics in heart grafts. METHODS.: Dark agouti hearts were transplanted to Lewis or control dark agouti rats on subtherapeutic doses of cyclosporin. Transplants were examined by immunohistology and quantitative immunofluorescence microscopy using lymphatic endothelial hyaluronan receptor-1 as a lymphatic marker and CD8 and CD68 as markers for cellular infiltration at selected intervals from 1 to 8 weeks posttransplantation. RESULTS.: Allograft inner myocardial lymphatic density decreased by more than 30-fold at 1 week and recovered to only 15% of the native level at 8 weeks posttransplantation. In contrast, allograft lymphatics in and near the epicardium showed no significant density decline but increased in size by more than 5-fold at 2 weeks, and sustained approximately 3-fold increase at 8 weeks posttransplantation. Lymphatic changes correlated temporally with the extent of T cell and macrophage infiltration in allografts, which peaked at 2 to 3 weeks posttransplantation. When grafts were retransplanted from allogeneic to isogeneic recipients at 3 weeks posttransplantation, inner lymphatic density returned close to native level within 2 weeks after retransplantation. CONCLUSIONS.: This is the first characterization of regional and morphologic effects of immunologic responses on heart lymphatics after transplantation. Elimination of alloimmune responses produces rapid restoration of inner lymphatic vessels, suggesting that lymphatics injured during rejection can recover when rejection is reversed during the posttransplantation course.
Uhrin, P., J. Zaujec, et al. (2010). “Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation.” Blood. Jan 28. [Epub ahead of print].
During embryonic development lymph sacs form from the cardinal vein, and sprout centrifugally to form mature lymphatic networks. Separation of the lymphatic from the blood circulation by a hitherto unknown mechanism is essential for the homeostatic function of the lymphatic system. O-glycans on the lymphatic endothelium have recently been suggested to be required for establishment and maintenance of distinct blood and lymphatic systems, primarily by mediating proper function of podoplanin. Here we show that this separation process critically involves platelet activation by podoplanin. We found that platelet aggregates build up in wild-type embryos at the separation zone of podoplanin positive lymph-sacs and cardinal veins, but not in podoplanin(-/-) embryos. Thus, podoplanin(-/-) mice develop a “non-separation” phenotype, characterized by a blood-filled lymphatic network after ∼E13.5, which however partially resolves in postnatal mice. The same embryonic phenotype is also induced by treatment of pregnant mice with acetyl salicylic acid, podoplanin blocking antibodies, or by inactivation of the kindlin-3 gene required for platelet aggregation. Therefore, interaction of endothelial podoplanin of the developing lymph-sac with circulating platelets from the cardinal vein is critical for separating the lymphatic from the blood vascular system.
von der Weid, P. Y. and M. Muthuchamy (2009). “Regulatory mechanisms in lymphatic vessel contraction under normal and inflammatory conditions.” Pathophysiology. Nov 27. [Epub ahead of print].
Weller, R. O., I. Galea, et al. (2009). “Pathophysiology of the lymphatic drainage of the central nervous system: Implications for pathogenesis and therapy of multiple sclerosis.” Pathophysiology. Nov 30. [Epub ahead of print].
Xu, Y., L. Yuan, et al. (2010). “Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3.” J Cell Biol
Vascular sprouting is a key process-driving development of the vascular system. In this study, we show that neuropilin-2 (Nrp2), a transmembrane receptor for the lymphangiogenic vascular endothelial growth factor C (VEGF-C), plays an important role in lymphatic vessel sprouting. Blocking VEGF-C binding to Nrp2 using antibodies specifically inhibits sprouting of developing lymphatic endothelial tip cells in vivo. In vitro analyses show that Nrp2 modulates lymphatic endothelial tip cell extension and prevents tip cell stalling and retraction during vascular sprout formation. Genetic deletion of Nrp2 reproduces the sprouting defects seen after antibody treatment. To investigate whether this defect depends on Nrp2 interaction with VEGF receptor 2 (VEGFR2) and/or 3, we intercrossed heterozygous mice lacking one allele of these receptors. Double-heterozygous nrp2vegfr2 mice develop normally without detectable lymphatic sprouting defects. In contrast, double-heterozygote nrp2vegfr3 mice show a reduction of lymphatic vessel sprouting and decreased lymph vessel branching in adult organs. Thus, interaction between Nrp2 and VEGFR3 mediates proper lymphatic vessel sprouting in response to VEGF-C.
Oncology
Cai, S., Y. Xie, et al. (2009). “Pharmacokinetics and disposition of a localized lymphatic polymeric hyaluronan conjugate of cisplatin in rodents.” J Pharm Sci. Dec 3. [Epub ahead of print].
Cohen, M. S., S. Cai, et al. (2009). “A novel intralymphatic nanocarrier delivery system for cisplatin therapy in breast cancer with improved tumor efficacy and lower systemic toxicity in vivo.” Am J Surg
Chen, Y. N. and Y. Gu (2009). “Vascular endothelial growth factor (VEGF)-D in association with VEGF receptor-3 in lymphatic metastasis of breast cancer.” Chin J Cancer
Damstra, R. J., E. A. Jagtman, et al. (2009). “Cancer-related secondary lymphoedema due to cutaneous lymphangitis carcinomatosa: clinical presentations and review of literature.” Eur J Cancer Care (Engl). Dec 17. [Epub ahead of print].
Hu, J., H. Ye, et al. (2010). “Deguelin-an inhibitor to tumor lymphangiogenesis and lymphatic metastasis by down-regulation of vascular endothelial cell growth factor-D in lung tumor model.” Int J Cancer. Feb 16. [Epub ahead of print].
Kubo, H., K. Hosono, et al. (2009). “Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis.” Biomed Pharmacother. Oct 20. [Epub ahead of print].
Sakuma, Y., T. Takeuchi, et al. (2009). “Lung adenocarcinoma cells floating in lymphatic vessels resist anoikis by expressing phosphorylated Src.” J Pathol. Dec 18. [Epub ahead of print].
Thelen, A., A. Scholz, et al. (2009). “Tumor-Associated Angiogenesis and Lymphangiogenesis Correlate With Progression of Intrahepatic Cholangiocarcinoma.” Am J Gastroenterol. Dec 8. [Epub ahead of print].
Tsutsui, S., A. Matsuyama, et al. (2010). “The Akt expression correlates with the VEGF-A and -C expression as well as the microvessel and lymphatic vessel density in breast cancer.” Oncol Rep
Werynska, B., P. Dziegiel, et al. (2009). “Role of lymphangiogenesis in lung cancer.” Folia Histochem Cytobiol
Yang, S., X. Zhu, et al. (2009). “Role of tumor-associated lymphatic endothelial cells in metastasis: A study of epithelial ovarian tumor in vitro.” Cancer Sci. Nov 14. [Epub ahead of print].
Tumor-associated lymphatic endothelial cells (TLEC) could play a key role in the process of tumor metastasis. The aim of this study was to investigate the effect of TLECs that were isolated from human epithelial ovarian tumor (EOT) on ovarian cancer cell line CAOV-3 in vitro. First, TLECs in EOT were detected by immunochemistry and flow cytometry, then marked by lymphatic endothelial cell (LEC) marker LYVE-1, isolated by magnetic beads, and cultured in vitro. The cells were identified by immunostaining of LEC markers LYVE-1, Prox-1, Podoplanin, VEGFR-3, and pan-endothelial cell marker CD31. TLECs from EOT can be detected, cultured, and identified in vitro successfully. The effects of TLECs on invasion and migration of CAOV-3 cells were investigated by 12-well Boyden chamber; the proliferation effect was studied by counting the Trypan blue exclusion cell number. Furthermore, changes in MMP-2/9 secreted by CAOV-3 cells treated with TLEC were shown using real-time PCR and zymography, and TIMP-1/2 was detected by real-time PCR. In vitro, TLECs can enhance invasion and migration of CAOV-3 cells, but have no significant effect on proliferation. It was clear that the expression of MMP-9 increased and TIMP-2 decreased in CAOV-3 cells treated by TLECs, and the increasing of MMP-9 was confirmed by zymography. TLECs from EOT can enhance migration and invasion of human ovarian carcinoma cell line in vitro, and the possible mechanism was through activation of MMP-9/TIMP-2. (Cancer Sci 2009).
Zhuang, Z., P. Jian, et al. (2009). “Altered phenotype of lymphatic endothelial cells induced by highly metastatic OTSCC cells contributed to the lymphatic metastasis of OTSCC cells.” Cancer Sci. Nov 18. [Epub ahead of print].
Reviews
Alexander, J. S. (2009). “Editorial: Lymphatic vessel functions in Health and Disease.” Pathophysiology. Dec 4. [Epub ahead of print].
Bahram, F. and L. Claesson-Welsh (2009). “VEGF-mediated signal transduction in lymphatic endothelial cells.” Pathophysiology. [16 December, Epub ahead of print].
Bates, D. O. (2009). “An interstitial hypothesis for breast cancer related lymphoedema.” Pathophysiology.
Bellini, C., M. Rutigliani, et al. (2009). “Nuchal translucency and lymphatic system maldevelopment.” J Perinat Med
Butler, M. G., S. Isogai, et al. (2009). “Lymphatic development.” Birth Defects Res C Embryo Today
Liersch, R., C. Biermann, et al. (2010). “Lymphangiogenesis in cancer: current perspectives.” Recent Results Cancer Res
Raica, M. and D. Ribatti (2010). “Targeting Tumor Lymphangiogenesis: An Update.” Curr Med Chem. Jan 21. [Epub ahead of print].
Ran, S., L. Volk, et al. (2009). “Lymphangiogenesis and lymphatic metastasis in breast cancer.” Pathophysiology. Dec 23. [Epub ahead of print].
Sainte-Marie, G. (2010). “The Lymph Node Revisited: Development, Morphology, Functioning, and Role in Triggering Primary Immune Responses.” Anat Rec (Hoboken)
Tammela, T. and K. Alitalo (2010). “Lymphangiogenesis: Molecular Mechanisms and Future Promise ” Cell
Clinical
Akhmetshina, A., J. Beer, et al. (2010). “Decreased lymphatic vessel counts in systemic sclerosis - Association with fingertip ulcers.” Arthritis Rheum. Feb 12. [Epub ahead of print].
Banta, D. P., N. Dandamudi, et al. (2009). “Yellow nail syndrome following thoracic surgery: A new association?” J Postgrad Med
Bunke, N., K. Brown, et al. (2009). “Phlebolymphemeda: usually unrecognized, often poorly treated.” Perspect Vasc Surg Endovasc Ther
Demirtas, Y., N. Ozturk, et al. (2009). “Comparison of Primary and Secondary Lower-Extremity Lymphedema Treated with Supermicrosurgical Lymphaticovenous Anastomosis and Lymphaticovenous Implantation.” J Reconstr Microsurg.
Fraunfelder, F. W. (2009). “Liquid nitrogen cryotherapy for conjunctival lymphangiectasia: a case series.” Trans Am Ophthalmol Soc
Maldonado, F., R. Cartin-Ceba, et al. (2010). “Medical and Surgical Management of Chylothorax and Associated Outcomes.” Am J Med Sci. Jan 29. [Epub ahead of print]
Vairo, G. L., S. J. Miller, et al. (2009). “Systematic review of efficacy for manual lymphatic drainage techniques in sports medicine and rehabilitation: an evidence-based practice approach.” J Man Manip Ther
van der Walt, J. C., T. J. Perks, et al. (2009). “Modified Charles procedure using negative pressure dressings for primary lymphedema: a functional assessment.” Ann Plast Surg
Vass, D. G., J. Hughes, et al. (2009). “Restorative and rejection-associated lymphangiogenesis after renal transplantation: friend or foe?” Transplantation
The review focuses on lymphangiogenesis as a possible contributor to interstitial fibrosis leading to chronic renal transplant injury, which culminates in the loss of 5% transplants annually. The process of lymphatic reconnection after renal transplantation and the mechanisms and mediators of lymphangiogenesis are explored in the context of new specific lymphatic markers. In addition, potentially exciting research avenues are examined, with the specific aim of determining whether new lymphatic formation is beneficial or detrimental to the transplanted kidney.
Wollina, U., G. Hansel, et al. (2010). “Using VAC to facilitate healing of traumatic wounds in patients with chronic lymphoedema.” J Wound Care
Vascular Anomalies
Arbiser, J. L., M. Y. Bonner, et al. (2009). “Hemangiomas, angiosarcomas, and vascular malformations represent the signaling abnormalities of pathogenic angiogenesis.” Curr Mol Med
Arneja, J. S. and J. B. Mulliken (2010). “Resection of amblyogenic periocular hemangiomas: indications and outcomes.” Plast Reconstr Surg
Benoit, M. M., P. E. North, et al. (2010). “Facial nerve hemangiomas: vascular tumors or malformations?” Otolaryngol Head Neck Surg
Bianca, S., G. Bartoloni, et al. (2010). “Familial Nuchal Cystic Hygroma without Fetal Effects: Genetic Counselling and Further Evidence for an Autosomal Recessive Subtype.” Congenit Anom (Kyoto). Feb 11. [Epub ahead of print].
De Simone, M., A. Lemos, et al. (2009). “Extended colonic lymphangiomatosis. Computed tomographic colonography in addition to optical endoscopy.” Minerva Chir
Eivazi, B., S. Wiegand, et al. (2010). “Orbital and periorbital vascular anomalies - an approach to diagnosis and therapeutic concepts.” Acta Otolaryngol. Jan 28. [Epub ahead of print].
Fay, A., J. Nguyen, et al. (2010). “Propranolol for isolated orbital infantile hemangioma.” Arch Ophthalmol
French, B., R. Bueno, Jr., et al. (2010). “Use of an arteriovenous fistula in facial reanimation after cystic hygroma resection.” Plast Reconstr Surg
Frieden, I. J. and B. A. Drolet (2009). “Propranolol for infantile hemangiomas: promise, peril, pathogenesis.” Pediatr Dermatol
Gedikbasi, A., K. Oztarhan, et al. (2009). “Multidisciplinary approach in cystic hygroma: prenatal diagnosis, outcome, and postnatal follow up.” Pediatr Int
Guo, S. and N. Ni (2010). “Topical Treatment for Capillary Hemangioma of the Eyelid Using {beta}-Blocker Solution.” Arch Ophthalmol
Heritier, S., M. Le Merrer, et al. (2010). “Retrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988–2009.” Orphanet J Rare Dis
Holak, E. J. and P. S. Pagel (2010). “Successful use of spinal anesthesia in a patient with severe Klippel-Trenaunay syndrome associated with upper airway abnormalities and chronic Kasabach-Merritt coagulopathy.” J Anesth. Jan 7. [Epub ahead of print].
Karakayali, F., C. Basaran, et al. (2010). “Spontaneous spleen rupture and rectus sheath hematoma in a patient with Klippel-Trenaunay syndrome: report of a case.” Surg Today
Khandpur, S. and V. K. Sharma (2010). “Utility of Intralesional Sclerotherapy with 3% Sodium Tetradecyl Sulphate in Cutaneous Vascular Malformations.” Dermatol Surg. Jan 19. [Epub ahead of print].
Kim, D. H., H. S. Seo, et al. (2010). “Lymphangiomatosis involving the inferior vena cava, heart, pulmonary artery and pelvic cavity.” Korean J Radiol
Kircher, M. F., E. Y. Lee, et al. (2010). “MRI findings of persistent sciatic artery associated with pelvic infantile hemangioma.” Clin Radiol
Kumar, K. R., K. Hon, et al. (2009). “Transient changes on brain magnetic resonance imaging in a patient with sturge-weber syndrome presenting with hemiparesis.” Neurologist
Leblanc, G. G., E. Golanov, et al. (2009). “Biology of vascular malformations of the brain.” Stroke
Liu, N. F., Q. Lu, et al. (2010). “Comparison of radionuclide lymphoscintigraphy and dynamic magnetic resonance lymphangiography for investigating extremity lymphoedema.” Br J Surg.
Markiewicz-Kijewska, M., W. Kasprzyk, et al. (2009). “Hemodynamic failure as an indication to urgent liver transplantation in infants with giant hepatic hemangiomas or vascular malformations–report of four cases.” Pediatr Transplant
Maturo, S. and C. Hartnick (2010). “Initial experience using propranolol as the sole treatment for infantile airway hemangiomas.” Int J Pediatr Otorhinolaryngol.
Przewratil, P., A. Sitkiewicz, et al. (2009). “Local serum levels of vascular endothelial growth factor in infantile hemangioma: Intriguing mechanism of endothelial growth.” Cytokine.
Ray, B. W. and I. R. Matthew (2009). “Point of Care. How do I manage a suspected oral vascular malformation?” J Can Dent Assoc
Rizzo, C., L. Brightman, et al. (2009). “Outcomes of childhood hemangiomas treated with the pulsed-dye laser with dynamic cooling: a retrospective chart analysis.” Dermatol Surg
Roomi, M. W., T. Kalinovsky, et al. (2009). “Antiangiogenic properties of a nutrient mixture in a model of hemangioma.” Exp Oncol
Tambe, K., V. Munshi, et al. (2009). “Relationship of infantile periocular hemangioma depth to growth and regression pattern.” J AAPOS
Tanwar, M., R. Sihota, et al. (2009). “Sturge-Weber Syndrome With Congenital Glaucoma and Cytochrome P450 (CYP1B1) Gene Mutations.” J Glaucoma.
Truong, M. T., K. W. Chang, et al. (2010). “Propranolol for the treatment of a life-threatening subglottic and mediastinal infantile hemangioma.” J Pediatr
Wu, J. K., O. Adepoju, et al. (2010). “A switch in Notch gene expression parallels stem cell to endothelial transition in infantile hemangioma.” Angiogenesis.
Yoon, H. S., J. H. Lee, et al. (2009). “Successful treatment of retroperitoneal infantile hemangioendothelioma with Kasabach-Merritt syndrome using steroid, alpha-interferon, and vincristine.” J Pediatr Hematol Oncol
You, L., M. Wu, et al. (2010). “Isolation and characterization of lymphatic endothelial cells from human glossal lymphangioma.” Oncol Rep