Abstract
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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.
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.
Discussion
These manuscripts discuss the role of CCBE1 in human lymphatic dysplasia. CCBE1, the Collagen And Calcium-Binding EGFDomain-Containing Protein 1, maps to chromosome 18q21.32.1 CCBE1 has been identified in zebrafish studies suggest its role as a “guidance molecule” in regulation of lymphagioblast budding and migration.2 Alders and colleagues as well as Connell et al. identified CCBE1 mutations in patients with generalized lymphatic dysplasia. These findings underscore the inter-relationship between basic science studies in lymphatic biology and their clinical correlations, and provide families with important genetic information which may affect future offspring.
1 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id= 612753
2Hogan, B. M.; Bos, F. L.; Bussmann, J.; Witte, M.; Chi, N. C.; Duckers, H. J.; Schulte-Merker, S.: Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nature Genet. 41: 396–398, 2009.
Basic Science
Albuquerque, R. J., T. Hayashi, et al. (2009). “Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth.” Nat Med. Sep;15(9):993–4.
Arimoto, J., Y. Ikura, et al. (2009). “Expression of LYVE-1 in sinusoidal endothelium is reduced in chronically inflamed human livers.” J Gastroenterol. [Epub ahead of print]
Ballou, B., L. A. Ernst, et al. (2009). “Imaging vasculature and lymphatic flow in mice using quantum dots.” Methods Mol Biol 574: 63–74.
Banerji, S., B. R. Hide, et al. (2009). “Distinctive properties of the hyaluronan binding domain in the lymphatic hyaluronan receptor Lyve-1 and their implications for receptor function.” J Biol Chem. [Epub ahead of print]
Bazigou, E., S. Xie, et al. (2009). “Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis.” Dev Cell 17(2): 175–186.
Berrih-Aknin, S., N. Ruhlmann, et al. (2009). “CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia.” Ann Neurol 66(4): 521–531.
Birke, K., E. Luetjen-Drecoll, et al. (2009). “Expression of Podoplanin and other Lymphatic Markers in the Human Anterior Eye Segment.” Invest Ophthalmol Vis Sci. [Epub ahead of print]
Bohlen, H. G., W. Wang, et al. (2009). “Phasic contractions of rat mesenteric lymphatics increase basal and phasic nitric oxide generation in vivo.” Am J Physiol Heart Circ Physiol. 297(4):H1319–28
Bourghardt Peebo, B., P. Fagerholm, et al. (2009). “In-vivo confocal microscopy reveals cellular-level detail of lymph vessels in live, unlabelled corneas.” Invest Ophthalmol Vis Sci. [Epub ahead of print]
Caruso, A., E. Caselli, et al. (2009). “U94 of human herpesvirus 6 inhibits in vitro angiogenesis and lymphangiogenesis.” Proc Natl Acad Sci U S A. 106(48):20446–51.
Human herpesvirus 6 (HHV-6) is a lymphotropic virus, but recent observations showed that also vascular endothelial cells (ECs) are susceptible to infection, both in vivo and in vitro. The observation that lymph nodes are a site of viral persistence suggests that lymphatic ECs (LECs) might be even more relevant for HHV-6 biology than vascular ECs. Here, we provide evidence that HHV-6 can infect LECs in vitro and establish a latent infection. Thus HHV-6 infection induces the loss of angiogenic properties both in LECs and in vascular ECs, as shown by the inability to form capillary-like structures and to seal wound scratches. The antiangiogenic effects observed in infected cells are associated to the expression of HHV-6 U94/rep, a latency-associated gene. In fact, transfection of U94/rep or addition of recombinant U94/REP protein to ECs inhibits the formation of in vitro capillary-like structures, reduces migration of ECs, and blocks angiogenesis, rendering rat aortic rings insensitive to VEGF-induced vasculogenetic activity. The ability of U94/rep to block different angiogenetic steps may lead to approaches in the potential control of the proliferation of blood and lymphatic vessels.
D'Amico, G., D. T. Jones, et al. (2009). “Regulation of lymphatic-blood vessel separation by endothelial Rac1.” Development 136(23): 4043–4053.
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.
D'Amico, G., E. Korhonen, et al. (2009). “Loss of Endothelial Tie1 Receptor Impairs Lymphatic Vessel Development.” Arterioscler Thromb Vasc Biol. [Epub ahead of print]
Dahl Ejby Jensen, L., R. Cao, et al. (2009). “Nitric oxide permits hypoxia-induced lymphatic perfusion by controlling arterial-lymphatic conduits in zebrafish and glass catfish.” Proc Natl Acad Sci U S A 106(43): 18408–18413.
The blood and lymphatic vasculatures are structurally and functionally coupled in controlling tissue perfusion, extracellular interstitial fluids, and immune surveillance. Little is known, however, about the molecular mechanisms that underlie the regulation of bloodlymphatic vessel connections and lymphatic perfusion. Here we show in the adult zebrafish and glass catfish (Kryptopterus bicirrhis) that blood-lymphatic conduits directly connect arterial vessels to the lymphatic system. Under hypoxic conditions, arterial-lymphatic conduits (ALCs) became highly dilated and linearized by NO-induced vascular relaxation, which led to blood perfusion into the lymphatic system. NO blockage almost completely abrogated hypoxia-induced ALC relaxation and lymphatic perfusion. These findings uncover mechanisms underlying hypoxia-induced oxygen compensation by perfusion of existing lymphatics in fish. Our results might also imply that the hypoxia-induced NO pathway contributes to development of progression of pathologies, including promotion of lymphatic metastasis by modulating arterial-lymphatic conduits, in the mammalian system.
Farace, F., M. Taylor, et al. (2009). “Quantification of circulating vascular endothelial growth factor receptor-3-positive lymphatic/vascular endothelial progenitor cells.” Clin Cancer Res 15(21): 6740; author reply 6740–6741.
Flister, M. J., A. Wilber, et al. (2009). “Inflammation induces lymphangiogenesis through upregulation of VEGFR-3 mediated by NF-{kappa}B and Prox1.” Blood. [Epub ahead of print]
Harada, K., T. Yamazaki, et al. (2009). “Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangiogenesis.” J Cell Sci 122(Pt 21): 3923–3930.
During lymphatic development, Prox1 plays central roles in the differentiation of blood vascular endothelial cells (BECs) into lymphatic endothelial cells (LECs), and subsequently in the maturation and maintenance of lymphatic vessels. However, the molecular mechanisms by which Prox1 elicits these functions remain to be elucidated. Here, we identified FoxC2 and angiopoietin-2 (Ang2), which play important roles in the maturation of lymphatic vessels, as novel targets of Prox1 in mouse embryonic-stem-cell-derived endothelial cells (MESECs). Furthermore, we found that expression of HoxD8 was significantly induced by Prox1 in MESECs, a finding confirmed in human umbilical vein endothelial cells (HUVECs) and human dermal LECs (HDLECs). In mouse embryos, HoxD8 expression was significantly higher in LECs than in BECs. In a model of inflammatory lymphangiogenesis, diameters of lymphatic vessels of the diaphragm were increased by adenovirally transduced HoxD8. We also found that HoxD8 induces Ang2 expression in HDLECs and HUVECs. Moreover, we found that HoxD8 induces Prox1 expression in HUVECs and that knockdown of HoxD8 reduces this expression in HDLECs, suggesting that Prox1 expression in LECs is maintained by HoxD8. These findings indicate that transcriptional networks of Prox1 and HoxD8 play important roles in the maturation and maintenance of lymphatic vessels.
Herbert, S. P., J. Huisken, et al. (2009). “Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation.” Science 326(5950): 294–298.
Blood vessels form de novo (vasculogenesis) or upon sprouting of capillaries from preexisting vessels (angiogenesis). With high-resolution imaging of zebrafish vascular development, we uncovered a third mode of blood vessel formation whereby the first embryonic artery and vein, two unconnected blood vessels, arise from a common precursor vessel. The first embryonic vein formed by selective sprouting of progenitor cells from the precursor vessel, followed by vessel segregation. These processes were regulated by the ligand EphrinB2 and its receptor EphB4, which are expressed in arterial-fated and venous-fated progenitors, respectively, and interact to orient the direction of progenitor migration. Thus, directional control of progenitor migration drives arterial-venous segregation and generation of separate parallel vessels from a single precursor vessel, a process essential for vascular development.
Hogan, B. M., R. Herpers, et al. (2009). “Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries.” Development 136(23): 4001–4009.
The development of arteries, veins and lymphatics from pre-existing vessels are intimately linked processes controlled by a number of well-studied reiteratively acting signalling pathways. To delineate the mechanisms governing vessel formation in vivo, we performed a forward genetic screen in zebrafish and isolated the mutant expando. Molecular characterisation revealed a loss-of-function mutation in the highly conserved kinase insert region of flt4. Consistent with previous reports, flt4 mutants were deficient in lymphatic vascular development. Recent studies have demonstrated a role for Flt4 in blood vessels and showed that Dll4 limits angiogenic potential by limiting Flt4 function in developing blood vessels. We found that arterial angiogenesis proceeded normally, yet the dll4 loss-of-function arterial hyperbranching phenotype was rescued, in flt4 signalling mutants. Furthermore, we found that the Flt4 ligand Vegfc drives arterial hyperbranching in the absence of dll4. Upon knockdown of dll4, intersegmental arteries were sensitised to increased vegfc levels and the overexpression of dll4 inhibited Vegfc/Flt4-dependent angiogenesis events. Taken together, these data demonstrate that dll4 functions to suppress the ability of developing intersegmental arteries to respond to Vegfc-driven Flt4 signalling in zebrafish. We propose that this mechanism contributes to the differential response of developing arteries and veins to a constant source of Vegfc present in the embryo during angiogenesis.
Jiang, Z., X. Hu, et al. (2009). “Harvesting and cryopreservation of lymphatic endothelial cells for lymphatic tissue engineering.” Cryobiology. [Epub ahead of print]
In order to provide a suitable source of cells for lymphatic tissue engineering, the present study was designed to investigate techniques for harvesting and cryopreservation of human dermal lymphatic endothelial cells (LECs) in vitro. The LECs were isolated from children's foreskins and then cultured in endothelial growth medium-2 MV (EGM-2-MV) with 5% FBS. The second passage LECs were suspended in cryopreservation solution containing 40% FBS and 10% Me(2)SO in EGM-2-MV, cooled to −80 degrees C at about 1 degrees C/min and stored in liquid nitrogen. Samples were thawed quickly in a 37 degrees C water bath, and the cryoprotectant was removed by serial elution. The membrane integrity of thawed LECs was determined by trypan blue staining exclusion, and their proliferation was evaluated using the MTT method. The expanded cells of two groups were identified using immunofluorescence staining and RT-PCR with lymphatic-specific markers such as Podoplanin and VEGFR-3. Uptake of fluorescent DiI-Ac-LDL and microtubular formation in three-dimensional cultures were used to detect the function of LECs. Flow cytometry was applied to identify cells and to measure the apoptosis rate as well. Cryopreservation resulted in a retrieval of 67+/−4% and an intact cell rate of 80+/−3%. The early apoptosis rate of thawed LECs (9.15+/−0.34%) was higher than that of fresh control LECs (5.31+/−0.23%). The growth curves of thawed LECs were similar to those of fresh LECs. The thawed LECs were propagated for at least 6-7 passages without alterations in phenotype and function. Highly purified LECs can be isolated by immunomagnetic beads from human dermis. The cryopreserved/thawed and recultivated LECs are proven to have high vitality and growth potential in vitro and may be considered suitable seed cells for lymphatic tissue engineering.
Karikoski, M., H. Irjala, et al. (2009). “Clever-1/Stabilin-1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation.” Eur J Immunol. [Epub ahead of print]
Clever-1/Stabilin-1 is a scavenger receptor present on lymphatic and sinusoidal endothelium as well as on a subset of type II macrophages. It is also induced on vasculature at sites of inflammation. However, its in vivo function has remained practically unknown and this work addresses those unknown aspects. We demonstrate using in vivo models that Clever-1/Stabilin-1 mediates migration of T and B lymphocytes to the draining lymph nodes in vivo and identify the adhesive epitope of the Clever-1/Stabilin-1 molecule responsible for the interaction between lymphocytes and lymphatic endothelium. Moreover, we demonstrate that Ab blocking of Clever-1/Stabilin-1 efficiently inhibits peritonitis in mice by decreasing the entrance of granulocytes by 50%, while migration of monocytes and lymphocytes into the inflamed peritoneum is prevented almost completely. Despite efficient anti-inflammatory activity the Ab therapy does not dramatically dampen immune responses against the bacterial and foreign protein Ag tested and bacterial clearance. These results indicate that anti-Clever-1/Stabilin-1 treatment can target two different arms of the vasculature - traffic via lymphatics and inflamed blood vessels.
Karunamuni, G., K. Yang, et al. (2009). “Expression of Lymphatic Markers During Avian and Mouse Cardiogenesis.” Anat Rec (Hoboken). [Epub ahead of print]
Li, X., T. Shimada, et al. (2009). “Ultrastructure Changes of Cardiac Lymphatics During Cardiac Fibrosis in Hypertensive Rats.” Anat Rec (Hoboken). 292(10):1612–8.
Lim, H. Y., J. M. Rutkowski, et al. (2009). “Hypercholesterolemic Mice Exhibit Lymphatic Vessel Dysfunction and Degeneration.” Am J Pathol. 175(3):1328–37.
Lymphatic vessels are essential for lipid absorption and transport. Despite increasing numbers of observations linking lymphatic vessels and lipids, little research has been devoted to address how dysregulation of lipid balance in the blood, ie, dyslipidemia, may affect the functional biology of lymphatic vessels. Here, we show that hypercholesterolemia occurring in apolipoprotein E-deficient (apoE(-/-)) mice is associated with tissue swelling, lymphatic leakiness, and decreased lymphatic transport of fluid and dendritic cells from tissue. Lymphatic dysfunction results in part from profound structural abnormalities in the lymphatic vasculature: namely, initial lymphatic vessels were greatly enlarged, and collecting vessels developed notably decreased smooth muscle cell coverage and changes in the distribution of lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1). Our results provide evidence that hypercholesterolemia in adult apoE(-/-) mice is associated with a degeneration of lymphatic vessels that leads to decreased lymphatic drainage and provides an explanation for why dendritic cell migration and, thus, immune priming, are compromised in hypercholesterolemic mice.
Ling, S., C. Qi, et al. (2009). “The expression of vascular endothelial growth factor C in transplanted corneas.” Curr Eye Res 34(7): 553–561.
Luo, G., X. Yu, et al. (2009). “LyP-1-conjugated nanoparticles for targeting drug delivery to lymphatic metastatic tumors.” Int J Pharm.
Active tumor targeting by biodegradable nanoparticles has been widely studied for cancer diagnosis and therapy. However, target-specific nanoparticles for drug delivery to lymphatic metastases have not been reported yet due to the lack of specific markers in the tumor lymphatics. Recently, peptide LyP-1 has been recognized for its specific home to tumors and their lymphatics. In this study, we tested the possibility of LyP-1 serving as a target-specific peptide of PEG-PLGA nanoparticles to tumor lymph metastases. LyP-1 was synthesized by using Boc-protected amino acids. The copolymers of maleimide-PEG-PLGA were formed by the conjugation of maleimide-PEG-NH(2) to PLGA-COOH, which were applied to prepare pegylated nanoparticles with mPEG-PLGA by means of double emulsion/solvent evaporation technique. LyP-1 with sulfhydryl group was conjugated to the maleimide function located at the distal end of PEG surrounding the nanoparticle surface. LyP-1-conjugated PEG-PLGA nanoparticle (LyP-1-NPs) had a round and regular shape with a diameter around 90nm. In vitro, cellular uptake of LyP-1-NPs was about four times of that of PEG-PLGA nanoparticles without LyP-1 (NPs). In vivo, the uptake of LyP-1-NPs in metastasis lymph nodes was about eight times of that of NPs. This study indicates that LyP-1-NP is a promising carrier for target-specific drug delivery to lymphatic metastatic tumors.
Matsuura, M., M. Onimaru, et al. (2009). “Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells.” Am J Pathol 175(4): 1709–1721.
Mouta-Bellum, C., A. Kirov, et al. (2009). “Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85alpha, p55alpha, and p50alpha.” Dev Dyn. 238(10):2670–9.
The phosphoinositide 3-kinase (PI3K) family has multiple vascular functions, but the specific regulatory isoform supporting lymphangiogenesis remains unidentified. Here, we report that deletion of the Pik3r1 gene, encoding the regulatory subunits p85alpha, p55alpha, and p50alpha impairs lymphatic sprouting and maturation, and causes abnormal lymphatic morphology, without major impact on blood vessels. Pik3r1 deletion had the most severe consequences among gut and diaphragm lymphatics, which share the retroperitoneal anlage, initially suggesting that the Pik3r1 role in this vasculature is anlage-dependent. However, whereas lymphatic sprouting toward the diaphragm was arrested, lymphatics invaded the gut, where remodeling and valve formation were impaired. Thus, cell-origin fails to explain the phenotype. Only the gut showed lymphangiectasia, lymphatic up-regulation of the transforming growth factor-beta co-receptor endoglin, and reduced levels of mature vascular endothelial growth factor-C protein. Our data suggest that Pik3r1 isoforms are required for distinct steps of embryonic lymphangiogenesis in different organ microenvironments, whereas they are largely dispensable for hemangiogenesis. Developmental Dynamics, 2009. (c) 2009 Wiley-Liss, Inc.
Nakao, S., K. Maruyama, et al. (2009). “Lymphangiogenesis and angiogenesis: concurrence and/or dependence? Studies in inbred mouse strains.” FASEB J. [Epub ahead of print]
Genetic background significantly affects angiogenesis in mice. However, lymphangiogenic response to growth factors (GFs) in different strains has not been studied. We report constitutive expression of corneal lymphatics that extends beyond the limits of normal limbal vessels. In untreated corneas, the total number (P = 0.006), the number above blood vessels (P = 10(-8)), and the area of preexisting lymphatics (P = 0.007) were significantly higher in C57BL/6 than in BALB/c mice. Normal corneas of three other strains, the nu/nu, 129E, and Black Swiss mice, showed in most parameters intermediate phenotypes. FGF-2(-/-) mice showed significantly less preexisting lymphatics than control (P = 0.009), which suggests a role for this GF in lymphatic development. VEGF-A-induced corneal lymphangiogenic response was significantly higher in BALB/c mice (P = 0.03), but it did not differ significantly in C57BL/6 mice, when compared to PBS-implanted control. FGFR-3 expression was higher in C57BL/6 than BALB/c mice, which suggests GF-receptor heterogeneity as a possible explanation for strain-dependent differences. The heterogeneity of preexisting lymphatic vessels in the limbal area significantly correlated with the extent of corneal lymphangiogenesis (VEGF-A: r = 0.7, P = 0.01; FGF-2: r = 0.96, P = 10(-5)) in BALB/c but not in C57BL/6 mice. Removal of conjunctival lymphatics did not affect GF-induced lymphangiogenesis. This work introduces physiological expression of lymphatics without blood vessels, which indicates that angiogenesis and lymphangiogenesis, even though intricately related, may occur independently. Furthermore, we show strain-dependence of normal and GF-induced lymphangiogenesis. These differences may affect disease development in various strains.
Niessen, K., G. Zhang, et al. (2009). “ALK1 signaling regulates early postnatal lymphatic vessel development.” Blood. [Epub ahead of print]
In vertebrates, endothelial cells form two hierarchical tubular networks, the blood vessels and the lymphatic vessels. Despite the difference in their structure and function, and genetic programs that dictate their morphogenesis, common signaling pathways have been recognized that regulate both vascular systems. ALK1 is a member of the TGFbeta type I family of receptors, and compelling genetic evidence suggests its essential role in regulating blood vascular development. Here we report that ALK1 signaling is intimately involved in lymphatic development. Lymphatic endothelial cells express key components of ALK1 pathway and respond robustly to ALK1 ligand stimulation in vitro. Blockade of ALK1 signaling results in defective lymphatic development in multiple organs of neonatal mice. We found that ALK1 signaling regulates the differentiation of lymphatic endothelial cells to influence the lymphatic vascular development and remodeling. Furthermore, simultaneous inhibition of ALK1 pathway increases apoptosis in lymphatic vessels caused by blockade of VEGFR3 signaling. Thus, our study reveals a novel aspect of ALK1 signaling in regulating lymphatic development, and suggests that targeting ALK1 pathway might provide additional control of lymphangiogenesis in human diseases.
Nisato, R. E., R. Buser, et al. (2009). “Lymphatic endothelial cells: establishment of primaries and characterization of established lines.” Methods Mol Biol 467: 113–126.
This chapter describes detailed methods for the isolation of primary human lymphatic endothelial cells from neonatal foreskin. We also provide protocols and information for their characterization and propagation. Isolation of primary human lymphatic endothelial cells requires a two-step process: mechanical and enzymatic digestion of human foreskins and cell sorting by fluorescence-activated cell sorting of CD31 +/podoplanin +/CD45- cells. Characterization of these cells requires an assessment of the expression of several markers specific for lymphatic endothelium. This is determined by fluorescence-activated cell sorting, immunocytochemistry, and polymerase chain reaction. All procedures are based on simple laboratory techniques and, with the exception of a cell sorter and the skills to use it, do not require specialized equipment.
Pan, M. R., T. M. Chang, et al. (2009). “Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells.” J Cell Sci. 122(Pt 18):3358–64.
Rehal, S., P. Blanckaert, et al. (2009). “Characterization of biosynthesis and modes of action of prostaglandin E(2) and prostacyclin in guinea pig mesenteric lymphatic vessels.” Br J Pharmacol. [Epub ahead of print]
Salgado, A. J., R. L. Reis, et al. (2009). “Adipose Tissue Derived Stem Cells Secretome: Soluble Factors and Their Roles in Regenerative Medicine.” Curr Stem Cell Res Ther. [Epub ahead of print]
Stem cells have been long looked at as possible therapeutic vehicles for different health related problems. Among the different existing stem cell populations, Adipose- derived Stem Cells (ASCs) have been gathering attention in the last 10 years. When compared to other stem cells populations and sources, ASCs can be easily isolated while providing simultaneously higher yields upon the processing of adipose tissue. Similar to other stem cell populations, it was initially thought that the main potential of ASCs for regenerative medicine approaches was intimately related to their differentiation capability. Although this is true, there has been an increasing body of literature describing the trophic effects of ASCs on the protection, survival and differentiation of variety of endogenous cells/tissues. Moreover, they have also shown to possess an immunomodulatory character. This effect is closely related to the ASCs' secretome and the soluble factors found within it. Molecules such as hepatocyte growth factor (HGF), granulocyte and macrophage colony stimulating factors, interleukins (ILs) 6, 7, 8 and 11, tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), adipokines and others have been identified within the ASCs' secretome. Due to its importance regarding future applications for the field of regenerative medicine, we aim, in the present review, to make a comprehensive analysis of the literature relating to the ASCs' secretome and its relevance to the immune and central nervous system, vascularization and cardiac regeneration. The concluding section will highlight some of the major challenges that remain before ASCs can be used for future clinical applications.
Shibuya, M. (2009). “Unique signal transduction of the VEGF family members VEGF-A and VEGF-E.” Biochem Soc Trans 37(Pt 6): 1161–1166.
Both VEGF (vascular endothelial growth factor)-A and Orf-virus-encoded VEGF-E bind and activate VEGFR (VEGF receptor)-2; however, only VEGF-A binds VEGFR-1. To understand the biological differences between VEGF-A and VEGF-E in vivo, we established transgenic mouse models. K14 (keratin-14)-promoter-driven VEGF-E transgenic mice showed a significant increase in mature blood vessels. However, K14-VEGF-A transgenic mice exhibited severe inflammation and oedema with increased angiogenesis, as well as lymphangiogenesis and lymph vessel dilatation. K14-VEGF-A transgenic mice deficient in VEGFR-1 signalling (K14-VEGF-A-tg/VEGFR-1 TK(-/-) mice) showed decreases in oedema and inflammation with less recruitment of macrophage-lineage cells, suggesting an involvement of VEGFR-1 in these adverse effects. VEGFE might be more useful than VEGFA for pro-angiogenic therapy.
Shimizu, K., S. Morikawa, et al. (2009). “Local lymphogenic migration pathway in normal mouse spleen.” Cell Tissue Res. [Epub ahead of print]
Although the immunological and hemodynamical significance of the spleen is of great importance, few reports detail the lymphatic vessels in this organ. We have used an immunohistochemical three-dimensional imaging technique to characterize lymphatic vessels in the normal mouse spleen and have successfully demonstrated their spatial relationship to the blood vascular system for the first time. Lymphatic markers, such as LYVE-1, VEGFR-3, and podoplanin, show different staining patterns depending on their location in the spleen. LYVE-1-positive lymphatic vessels run reverse to the arterial blood flow along the central arteries in the white pulp and trabecular arteries and exit the spleen from the hilum. These lymphatic vessels are surrounded by type IV collagen, indicating that they are collecting lymphatic vessels rather than lymphatic capillaries. Podoplanin is expressed not only in lymphatic vessels, but also in stromal cells in the white pulp. These podoplanin-positive cells form fine meshworks surrounding the lymphatic vessels and central arteries. Following intravenous transplantation of lymphocytes positive for green fluorescent protein (GFP(+)) into normal recipient mice, donor cells appear in the meshworks within 1 h and accumulate in the lymphatic vessels within 6 h after injection. The GFP(+) cells further accumulate in a draining celiac lymph node through the efferent lymphatic vessels from the hilum. These meshworks might therefore act as an extravascular lymphatic pathway and, together with ordinary lymphatic vessels, play a primary role in the cell traffic of the spleen, additional to the blood circulatory system.
Shin, S. B., H. Y. Cho, et al. (2009). “Preparation and evaluation of tacrolimus-loaded nanoparticles for lymphatic delivery.” Eur J Pharm Biopharm. [Epub ahead of print]
In an effort to improve lymphatic targeting efficiency and reduce the toxicity of tacrolimus, the emulsification-diffusion method was used to load the drug into nanoparticles (NP). Poly (lactide-co-glycolide) (PLGA) and PLGA surface-modified with poly (ethylene glycol) (PEG) were used as polymers. Mean particle size and drug encapsulation efficiency of PLGA were 218 +/− 51 nm and 60.0 +/− 1.2% and for PEG-PLGA NP were 220 +/− 33 nm and 60.3 +/− 2.0%. NP were characterized by thermal analyzer and X-ray diffractometry (XRD), and their shapes were observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). In vitro release profiles were affected by the pH of dissolution media. The prepared NP and commercial product of tacrolimus (Prograf((R)) inj.) were intravenously administered to rats to compare their pharmacokinetic characteristics and lymphatic targeting efficiency. The area under the whole blood concentration-time curve (AUC), mean residence time (MRT) and total clearance (CL(t)) of PEG-PLGA NP were significantly different (P < 0.05) compared with those of Prograf((R)) inj., and lymphatic targeting efficiencies of both NP formulations at the mesenteric lymph node significantly increased (P < 0.05). These results showed that the prepared tacrolimus-loaded NP are good possible candidates as a lymphatic delivery system of tacrolimus.
Skobe, M. and R. Dana (2009). “Blocking the path of lymphatic vessels.” Nat Med 15(9): 993–994.
Takahashi, M., E. Suzuki, et al. (2009). “Adipose Tissue-Derived Stem Cells Inhibit Neointimal Formation in a Paracrine Fashion in Rat Femoral Artery.” Am J Physiol Heart Circ Physiol. [Epub ahead of print]
Subcutaneous adipose tissue contains a lot of stem cells (Adipose-derived stem cells; ASC) that can differentiate into a variety of cell lineages. In this study, we isolated ASC from Wistar rats and examined whether ASC would efficiently differentiate into vascular endothelial cells (EC) in vitro. We also administered ASC in a wire injury model of rat femoral artery, and examined their effects. ASC expressed CD29 and CD90, but not CD34, suggesting that ASC resemble bone marrow-derived mesenchymal stem cells. When induced to differentiate into EC with endothelial growth medium (EGM), ASC expressed Flt-1, but not Flk-1 or mature endothelial cell markers such as CD31 and VE-cadherin. ASC produced angiopoietin-1 when they were cultured in EGM. ASC stimulated migration of EC, as assessed by chemotaxis assay. When ASC that were cultured in EGM were injected in the femoral artery, ASC potently and significantly inhibited neointimal formation without being integrated in the endothelial layer. EGM-treated ASC significantly suppressed neointimal formation even when they were administered from the adventitial side. ASC administration significantly promoted endothelial repair. These results suggested that although ASC appear to have little capacity to differentiate into mature EC, ASC have the potential to secrete paracrine factorsthat stimulate endothelial repair. Our results also suggested that ASC inhibited neointimal formation via their paracrine effect of stimulation of EC migration in situ rather than direct integration into the endothelial layer. Key words: Adipose tissue, stem cells, vascular endothelial cells, restenosis.
Tilki, D., H. P. Hohn, et al. (2009). “Emerging biology of vascular wall progenitor cells in health and disease.” Trends Mol Med 15(11): 501–509.
New blood vessels are formed through angiogenesis and postnatal vasculogenesis. Thus, it is essential to identify vascular stem and progenitor cell niches and the mechanisms governing their role in blood vessel formation. Although much is known about circulating and bone marrow-derived endothelial progenitor cells (EPCs), little is known about the vascular wall as an EPC niche. Experimental evidence strongly suggests that EPCs, as well as other stem and progenitor cells, reside in distinct zones of the vessel wall, such as within the subendothelial space and in the so-called “vasculogenic zone” within the vascular adventitia. In this review, we discuss the potential implications of different types of vascular wall resident stem and progenitor cells in health and disease.
Tsuka, N., M. Motokawa, et al. (2009). “Fms-like tyrosine kinase (Flt)-4 signaling participates in osteoclast differentiation in osteopetrotic (op/op) mice.” Biomed Res 30(1): 31–37.
von der Weid, P. Y., M. Rahman, et al. (2008). “Spontaneous transient depolarizations in lymphatic vessels of the guinea pig mesentery: pharmacology and implication for spontaneous contractility.” Am J Physiol Heart Circ Physiol 295(5): H1989–2000.
Wu, F. T., M. O. Stefanini, et al. (2009). “Modeling of growth factor-receptor systems from molecular-level protein interaction networks to whole-body compartment models.” Methods Enzymol 467: 461–497.
Wu, F. T., M. O. Stefanini, et al. (2009). “A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.” PLoS One 4(4): e5108.
Vascular endothelial growth factor (VEGF), through its activation of cell surface receptor tyrosine kinases including VEGFR1 and VEGFR2, is a vital regulator of stimulatory and inhibitory processes that keep angiogenesis–new capillary growth from existing microvasculature–at a dynamic balance in normal physiology. Soluble VEGF receptor-1 (sVEGFR1)–a naturally-occurring truncated version of VEGFR1 lacking the transmembrane and intracellular signaling domains–has been postulated to exert inhibitory effects on angiogenic signaling via two mechanisms: direct sequestration of angiogenic ligands such as VEGF; or dominant-negative heterodimerization with surface VEGFRs. In pre-clinical studies, sVEGFR1 gene and protein therapy have demonstrated efficacy in inhibiting tumor angiogenesis; while in clinical studies, sVEGFR1 has shown utility as a diagnostic or prognostic marker in a widening array of angiogenesis-dependent diseases. Here we developed a novel computational multi-tissue model for recapitulating the dynamic systemic distributions of VEGF and sVEGFR1. Model features included: physiologically-based multi-scale compartmentalization of the human body; inter-compartmental macromolecular biotransport processes (vascular permeability, lymphatic drainage); and molecularly-detailed binding interactions between the ligand isoforms VEGF(121) and VEGF(165), signaling receptors VEGFR1 and VEGFR2, non-signaling co-receptor neuropilin-1 (NRP1), as well as sVEGFR1. The model was parameterized to represent a healthy human subject, whereupon we investigated the effects of sVEGFR1 on the distribution and activation of VEGF ligands and receptors. We assessed the healthy baseline stability of circulating VEGF and sVEGFR1 levels in plasma, as well as their reliability in indicating tissue-level angiogenic signaling potential. Unexpectedly, simulated results showed that sVEGFR1 - acting as a diffusible VEGF sink alone, i.e., without sVEGFR1-VEGFR heterodimerization–did not significantly lower interstitial VEGF, nor inhibit signaling potential in tissues. Additionally, the sensitivity of plasma VEGF and sVEGFR1 to physiological fluctuations in transport rates may partially account for the heterogeneity in clinical measurements of these circulating angiogenic markers, potentially hindering their diagnostic reliability for diseases.
Wu, M., L. Han, et al. (2009). “Development and characterization of a novel method for the analysis of gene expression patterns in lymphatic endothelial cells derived from primary breast tissues.” J Cancer Res Clin Oncol. [Epub ahead of print]
The combined application of laser capture microdissection (LCM) and gene expression microarray analysis has rarely been used to study lymphangiogenesis because of technical obstacles. In this study, a novel method using this combined approach was developed to analyze the gene expression patterns in lymphatic endothelial cells (LECs). First, LECs were identified in frozen sections using rapid immunostaining and isolated using LCM, and then intact RNA from the LECS was purified and amplified. The expression profile was analyzed using microarray analysis, and the expression of selected genes (Sema4C and C4orf7) was evaluated by quantitative RT-PCR (qRT-PCR) and immunofluorescence assays. These results indicate that the combination of RIHC-LCM, two-round linear amplification of the small sample RNA and genome-wide microarray analysis allows gene expression profiling of tumor LECs, which provides a powerful tool for the study of molecular details in human lymphangiogenesis-related diseases, such as lymphatic metastasis of human breast cancers. These findings also suggest that the LEC-specific genes Sema4C and C4orf7 may play an important role in the oncogenesis of human breast cancer.
Yucel, Y. H., M. G. Johnston, et al. (2009). “Identification of lymphatics in the ciliary body of the human eye: A novel “uveolymphatic” outflow pathway.” Exp Eye Res. 89(5):810–9.
Impaired aqueous humor flow from the eye may lead to elevated intraocular pressure and glaucoma. Drainage of aqueous fluid from the eye occurs through established routes that include conventional outflow via the trabecular meshwork, and an unconventional or uveoscleral outflow pathway involving the ciliary body. Based on the assumption that the eye lacks a lymphatic circulation, the possible role of lymphatics in the less well defined uveoscleral pathway has been largely ignored. Advances in lymphatic research have identified specific lymphatic markers such as podoplanin, a transmembrane mucin-type glycoprotein, and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). Lymphatic channels were identified in the human ciliary body using immunofluorescence with D2-40 antibody for podoplanin, and LYVE-1 antibody. In keeping with the criteria for lymphatic vessels in conjunctiva used as positive control, D2-40 and LYVE-1-positive lymphatic channels in the ciliary body had a distinct lumen, were negative for blood vessel endothelial cell marker CD34, and were surrounded by either discontinuous or no collagen IV-positive basement membrane. Cryo-immunogold electron microscopy confirmed the presence D2-40-immunoreactivity in lymphatic endothelium in the human ciliary body. Fluorescent nanospheres injected into the anterior chamber of the sheep eye were detected in LYVE-1-positive channels of the ciliary body 15, 30, and 45 min following injection. Four hours following intracameral injection, Iodine-125 radio-labeled human serum albumin injected into the sheep eye (n = 5) was drained preferentially into cervical, retropharyngeal, submandibular and preauricular lymph nodes in the head and neck region compared to reference popliteal lymph nodes (P < 0.05). These findings collectively indicate the presence of distinct lymphatic channels in the human ciliary body, and that fluid and solutes flow at least partially through this system. The discovery of a uveolymphatic pathway in the eye is novel and highly relevant to studies of glaucoma and other eye diseases.
Reviews
Casteilla, L., V. Planat-Benard, et al. (2009). “Vascular and Endothelial Regeneration.” Curr Stem Cell Res Ther. [Epub ahead of print]
Adipose tissue is the final tissue to develop and is strongly involved in energy homeostasis. It can represent up to 50% of body weight in obesity. Beside its metabolic role, endocrine functions appeared to play a key role in interconnecting adipose tissue with other tissues of the organism and in numerous physiological functions. The presence of adipocyte progenitors has long been demonstrated throughout life in the stromal fraction of adipose tissue. Now, it appears that these cells are multipotent and share numerous features with mesenchymal stem cells (MSC) derived from bone marrow. They also display some specificities and a strong pro-angiogenic potential. Altogether, these data emphasize the need to reconsider the potential of adipose tissue. Moreover, since fat pads are easy to sample, numerous and promising perspectives are now opening up in regenerative medicine, particularly in ischemic situations.
Cui, Y. (2009). “The role of lymphatic vessels in the heart.” Pathophysiology. [Epub ahead of print]
Although cardiac lymphatic vessels have been described for over three centuries, research progress on the role of cardiac lymphatic vessels in regulating cardiac physiology and their disturbances in the pathogenesis of cardiac disease has progressed very slowly, largely due to technical challenges in developing both animal models and cardiac lymphatic vascular imaging technologies. This review summarizes evidence showing that blocking cardiac lymph flow may contribute to several forms of cardiac injury including cardiac lymphedema, cardiac valvular deformation, coronary arterial injury, conduction disturbances, myocardial injury, and poor heart performance in animal and human heart studies. Conversely, improving cardiac lymph flow may have beneficial effects on heart function after heart attack (myocardial infarction). In addition, this review summarizes recent hypotheses about the forces generating cardiac lymph flow, in which the role of both the subepicardial and mid-myocardial myocytes synchronized contractions causing lymph flow is discussed. Lastly, possible mechanisms of blood vessel injury caused by the failure of perivascular lymphatic remodeling are discussed.
Kawai, Y. and T. Ohhashi (2009). “Topics of physiological and pathophysiological functions of lymphatics.” Curr Mol Med 9(8): 942–953.
Rutkowski, J. M., K. E. Davis, et al. (2009). “Mechanisms of obesity and related pathologies: the macro- and microcirculation of adipose tissue.” FEBS J 276(20): 5738–5746.
Adipose tissue is an endocrine organ made up of adipocytes, various stromal cells, resident and infiltrating immune cells, and an extensive endothelial network. Adipose secretory products, collectively referred to as adipokines, have been identified as contributors to the negative consequences of adipose tissue expansion that include cardiovascular disease, diabetes and cancer. Systemic blood circulation provides transport capabilities for adipokines and fuels for proper adipose tissue function. Adipose tissue microcirculation is heavily impacted by adipose tissue expansion, some adipokines can induce endothelial dysfunction, and angiogenesis is necessary to counter hypoxia arising as a result of tissue expansion. Tumors, such as invasive lesions in the mammary gland, co-opt the adipose tissue microvasculature for local growth and metastatic spread. Lymphatic circulation, an area that has received little metabolic attention, provides an important route for dietary and peripheral lipid transport. We review adipose circulation as a whole and focus on the established and potential interplay between adipose tissue and the microvascular endothelium.
Wilting, J., J. Becker, et al. (2009). “Lymphatics and Inflammation.” Curr Med Chem. 16(34):4581–92.
Inflammation is a local or systemic tissue reaction caused by external or internal stimuli with the objective to remove the noxa, inhibit its further dissemination and eventually repair damaged tissue. Blood vessels and perivascular connective tissue are important regulators of the inflammatory process. After a short initial ischemic phase, inflamed tissue is characterized by hyperaemia and increased permeability of capillaries. Therefore, blood vessels have been in the focus of inflammation research for quite some time, whereas lymphatic vessels have been neglected. Their reactivity is not immediately obvious, and, their identification within the tissue has hardly been possible until lymphatic endothelial cell (LEC)-specific molecules have been identified a few years ago. This has opened up the possibility to study lymphatics in normal and diseased tissues, and to isolate LECs for transcriptome and proteome analyses. Initial studies now provide evidence that lymphatics are not just a passive route for circulating lymphocytes, but seem to be directly involved in both the induction and the resolution of inflammation. This review provides a summary on the basics of inflammation, the structure of lymphatics and their molecular markers, human inflammation-associated diseases and their relation to lymphatics, animal models to study the interaction of lymphatics and inflammation, and finally inflammation-associated molecules expressed in LECs. The integration of lymphatics into inflammation research opens up an exciting new field with great clinical potential.
Oncology
Fu, M. R. and M. Rosedale (2009). “Breast Cancer Survivors' Experiences of Lymphedema-Related Symptoms.” J Pain Symptom Manage. [Epub ahead of print].
Goldblatt, M., J. T. Huggins, et al. (2009). “Dasatinib-induced pleural effusions: a lymphatic network disorder?” Am J Med Sci 338(5): 414–417.
Dasatanib, which has been approved for rescue therapy for patients with imatinib-resistant chronic myelogenous leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia, is a novel, orally available multitargeted kinase inhibitor of BCR-ABL and SRC family kinases (Quintas-Cardama et al, J Clin Oncol 2007;25:3908-14). It binds to both active and inactive conformations of the ABL gene and is 325 times more potent than imatinib in inhibiting the growth of BCR/ABL cells in vitro (Morelock and Sahn, Chest 1999;116:212-21; Huggins and Sahn, Clin Chest Med 2004;25:141-53). Although dasatinib is a generally well-tolerated drug in the treatment of Philadelphia chromosome positive hematopoetic malignancies, pleural effusions have been frequently noted and have been reported in up to 35% of patients (Sahn SA. Drug-induced pleural disease. In: Camus P, Rosenow E, editors. Drug-induced iatrogenic lung disease. London: Hodder Arnold; 2009). Although there have been numerous reports of effusions, none have provided complete pleural fluid analysis; therefore, we report 2 patients with dasatinib-induced pleural effusion with complete pleural fluid analysis.
Lau, R. W. and G. L. Cheing (2009). “Managing postmastectomy lymphedema with low-level laser therapy.” Photomed Laser Surg 27(5): 763–769.
Sapoznik, S., B. Cohen, et al. (2009). “Gonadotropin-Regulated Lymphangiogenesis in Ovarian Cancer Is Mediated by LEDGF-Induced Expression of VEGF-C.” Cancer Res. [Epub ahead of print]
The risk and severity of ovarian carcinoma, the leading cause of gynecologic malignancy death, are significantly elevated in postmenopausal women. Ovarian failure at menopause, associated with a reduction in estrogen secretion, results in an increase of the gonadotropic luteinizing hormone (LH) and follicle-stimulating hormone (FSH), suggesting a role for these hormones in facilitating the progression of ovarian carcinoma. The current study examined the influence of hormonal stimulation on lymphangiogenesis in ovarian cancer cells. In vitro stimulation of ES2 ovarian carcinoma cells with LH and FSH induced expression of vascular endothelial growth factor (VEGF)-C. In vivo, ovariectomy of mice resulted in activation of the VEGF-C promoter in ovarian carcinoma xenografts, increased VEGF-C mRNA level, and enhanced tumor lymphangiogenesis and angiogenesis. Seeking the molecular mechanism, we examined the role of lens epithelium-derived growth factor (LEDGF/p75) and the possible contribution of its putative target, a conserved stress-response element identified in silico in the VEGF-C promoter. Using chromatin immunoprecipitation, we showed that LEDGF/p75 indeed binds the VEGF-C promoter, and binding is augmented by FSH. A corresponding hormonally regulated increase in the LEDGF/p75 mRNA and protein levels was observed. Suppression of LEDGF/p75 expression using small interfering RNA, suppression of LH and FSH production using the gonadotropin-releasing hormone antagonist cetrorelix, or mutation of the conserved stress-response element suppressed the hormonally induced expression of VEGF-C. Overall, our data suggest a possible role for elevated gonadotropins in augmenting ovarian tumor lymphangiogenesis in postmenopausal women.
Schoppmann, S. F., D. Tamandl, et al. (2009). “HER2/neu expression correlates with vascular endothelial growth factor-C and lymphangiogenesis in lymph node-positive breast cancer.” Ann Oncol. [Epub ahead of print]
Vetrano, S., E. M. Borroni, et al. (2009). “The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6.” Gut. [Epub ahead of print]
Yang, S., H. Cheng, et al. (2009). “PlGF expression in pre-invasive and invasive lesions of uterine cervix is associated with angiogenesis and lymphangiogenesis.” APMIS 117(11): 831–838.
Clinical
Bellini, C., E. Di Battista, et al. (2009). “The role of lymphoscintigraphy in the diagnosis of lymphedema in Turner syndrome.” Lymphology 42(3): 123–129.
Curry, J. M., W. H. Ezzat, et al. (2009). “Thyroid lymphosonography: a novel method for evaluating lymphatic drainage.” Ann Otol Rhinol Laryngol 118(9): 645–650.
Lom, J., T. Dhere, et al. (2009). “Intestinal Lymphangiectasia Causing Massive Gastrointestinal Bleed.” J Clin Gastroenterol.
Lu, Y. Y., J. F. Wu, et al. (2009). “Hypocalcemia and tetany caused by vitamin D deficiency in a child with intestinal lymphangiectasia.” J Formos Med Assoc 108(10): 814–818.
Luongo, J. A., L. R. Scalcione, et al. (2009). “Progression of clinically stable lymphedema on lymphoscintigraphy.” Clin Nucl Med 34(9): 585–588.
Manduch, M., A. M. Oliveira, et al. (2009). “Massive localised lymphoedema: a clinicopathological study of 22 cases and review of the literature.” J Clin Pathol 62(9): 808–811.
Olszewski, W. L., P. J. Ambujam, et al. (2009). “Where do lymph and tissue fluid accumulate in lymphedema of the lower limbs caused by obliteration of lymphatic collectors?” Lymphology 42(3): 105–111.
Raman, S. P., S. N. Pipavath, et al. (2009). “Imaging of thoracic lymphatic diseases.” AJR Am J Roentgenol 193(6): 1504–1513.
Steinacher, I., B. Lamprecht, et al. (2009). “Successful surgical treatment of thoracic multiorgan lymphangiomatosis.” Wien Klin Wochenschr 121(19-20): 644–647.
Suresh, N., R. Ganesh, et al. (2009). “Primary intestinal lymphangiectasia.” Indian Pediatr 46(10): 903–906.
Tobbia, D., J. Semple, et al. (2009). “Experimental assessment of autologous lymph node transplantation as treatment of postsurgical lymphedema.” Plast Reconstr Surg 124(3): 777–786.
Topol, M. and A. Maslon (2009). “Some variations in lymphatic drainage of selected bronchopulmonary segments in human lungs.” Ann Anat. 191(6):568–74.
Vignes, S., M. Arrault, et al. (2009). “Subjective Assessment of Pregnancy Impact on Primary Lower Limb Lymphedema.” Angiology. [Epub ahead of print]
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 9(8): 929–934.
Angiogenesis is a major factor in the development of benign, inflammatory, and malignant processes of the skin. Endothelial cells are the effector cells of angiogenesis, and understanding their response to growth factors and inhibitors is critical to understanding the pathogenesis and treatment of skin disease. Hemangiomas, benign tumors of endothelial cells, represent the most common tumor of childhood. In our previous studies, we have found that tumor vasculature in human solid tumors expresses similarities in signaling to that of hemangiomas, making the knowledge of signaling in hemangiomas widely applicable. These similarities include expression of reactive oxygen, NFkB and akt in tumor vasculature. Furthermore, we have studied malignant vascular tumors, including hemangioendothelioma and angiosarcoma and have shown distinct signaling abnormalities in these tumors. The incidence of these tumors is expected to rise due to environmental insults, such as radiation and lumpectomy for breast cancer, dietary and industrial carcinogens (hepatic angiosarcoma), and chronic ultraviolet exposure and potential Agent Orange exposure. I hypothesize that hemangiomas, angiosarcomas, and vascular malformations represent the extremes of signaling abnormalities seen in pathogenic angiogenesis.
Buckmiller, L. M. (2009). “Propranolol treatment for infantile hemangiomas.” Curr Opin Otolaryngol Head Neck Surg 17(6): 458–459.
Colonna, V., L. Resta, et al. (2009). “Placental hypoxia and neonatal haemangioma: clinical and histological observations.” Br J Dermatol. [Epub ahead of print]
Coombs, P. R., P. A. James, et al. (2009). “Sonographic identification of lower limb venous hypoplasia in the prenatal diagnosis of Klippel-Trenaunay syndrome.” Ultrasound Obstet Gynecol. 34(6):727–729.
Cordisco, M. R. (2009). “An update on lasers in children.” Curr Opin Pediatr 21(4): 499–504.
Dayicioglu, D., E. G. Martell, et al. (2009). “Vascular anomalies of the upper extremity in children.” J Craniofac Surg 20(4): 1025–1029.
Dompmartin, A., F. Ballieux, et al. (2009). “Elevated D-dimer level in the differential diagnosis of venous malformations.” Arch Dermatol 145(11): 1239–1244.
Dupond, J. L., L. Bermont, et al. (2009). “Plasma VEGF Determination in Disseminated Lymphangiomatosis-Gorham-Stout Syndrome. A marker of activity? A case report with a 5 years follow-up.” Bone. [Epub ahead of print]
Disseminated lymphangiomatosis and Gorham-Stout disease are being considered as two forms of a single rare disease, characterized by a proliferation of lymphatic vessels, triggered by lymphangiogenic factors. There is no biological marker of the disease. Plasma VEGF might be a useful tool since the recent demonstration of its pivotal role in the mechanism of this disease. A 45-year-old woman with a history of disseminated lymphangiomatosis involving mediastinum, retroperitoneum, spleen and systemic bones for 29 years, was treated with Interferon alpha 2b at a dosage of 7,5 to 15 millions IU 3 times a week for 5 years. Plasma VEGF quantification was performed twice a year and showed a markedly increase before therapy which normalize after 18 months of treatment with Interferon. The normalization of plasma VEGF is correlated with the clinical improvement objectively appraised by a marked reduction of spleen lesions and significant improvement of the other damages in soft tissues and bones. Thus, we conclude that plasma VEGF determination should be considered for diagnosis and follow-up of the course and the treatment of disseminated lymphangiomatosis Gorham-Stout disease.
Frieden, I. J., M. Rogers, et al. (2009). “Conditions masquerading as infantile haemangioma: Part 2.” Australas J Dermatol 50(3): 153-168; quiz 169–170.
Fuchs, J., S. W. Warmann, et al. (2009). “Impact of Virtual Imaging Procedures on Treatment Strategies in Children With Hepatic Vascular Malformations.” J Pediatr Gastroenterol Nutr. [Epub ahead of print]
Happle, R. (2009). “Superimposed Segmental Hemangioma of Infancy.” Dermatology. [Epub ahead of print]
Kim, N. R., S. K. Lee, et al. (2009). “Primary intestinal lymphangiectasia successfully treated by segmental resections of small bowel.” J Pediatr Surg 44(10): e13–17.
Lawley, L. P., E. Siegfried, et al. (2009). “Propranolol treatment for hemangioma of infancy: risks and recommendations.” Pediatr Dermatol 26(5): 610–614.
Leblanc, G. G., E. Golanov, et al. (2009). “Biology of Vascular Malformations of the Brain.” Stroke. 40(12):e694–702.
Lee, S. J., D. J. Shin, et al. (2009). “A fraction of deep vascular birthmarks are true deep hemangiomas of infancy.” Int J Dermatol 48(8): 817–821.
Marsciani, A., R. Pericoli, et al. (2009). “Massive response of severe infantile hepatic hemangioma to propanolol.” Pediatr Blood Cancer. 54(1):176.
Metry, D., G. Heyer, et al. (2009). “Consensus Statement on Diagnostic Criteria for PHACE Syndrome.” Pediatrics 124(5): 1447–1456.
Metry, D. W., M. C. Garzon, et al. (2009). “PHACE syndrome: current knowledge, future directions.” Pediatr Dermatol 26(4): 381–398.
Mohamed, A. M., T. F. Elwakil, et al. (2009). “Cyclin D1 gene amplification in proliferating haemangioma.” Cell Tissue Res 338(1): 107–115.
Pascual-Castroviejo, I. C., S. I. Pascual-Pascual, et al. (2009). “Major and Minor Arterial Malformations in Patients With Cutaneous Vascular Abnormalities.” J Child Neurol. [Epub ahead of print]
Redondo, P., G. Bastarrika, et al. (2009). “Efficacy and safety of microfoam sclerotherapy in a patient with Klippel-Trenaunay syndrome and a patent foramen ovale.” Arch Dermatol 145(10): 1147–1151.
Ruiz, D. S., H. Yilmaz, et al. (2009). “Cerebral developmental venous anomalies: current concepts.” Ann Neurol 66(3): 271–283.
Sharan, S., B. Swamy, et al. (2009). “Port-wine vascular malformations and glaucoma risk in Sturge-Weber syndrome.” J AAPOS 13(4): 374–378.
Wang, S., J. H. Lang, et al. (2009). “Venous malformations of the female lower genital tract.” Eur J Obstet Gynecol Reprod Biol 145(2): 205–208.
Wiegand, S., B. Eivazi, et al. (2009). “Microcystic lymphatic malformations of the tongue: diagnosis, classification, and treatment.” Arch Otolaryngol Head Neck Surg 135(10): 976–983.
Wolfe, S. Q., H. Farhat, et al. (2009). “Transarterial embolization of a scalp hemangioma presenting with Kasabach-Merritt syndrome.” J Neurosurg Pediatr 4(5): 453–457.
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. 31(12):952–4.