Abstract Hypoxia and lymphangiogenesis are closely related processes that play a pivotal role in tumor invasion and metastasis. Intratumoral hypoxia is exacerbated as a result of oxygen consumption ...by rapidly proliferating tumor cells, insufficient blood supply and poor lymph drainage. Hypoxia induces functional responses in lymphatic endothelial cells (LECs), including cell proliferation and migration. Multiple factors (e.g., ET-1, AP-1, C/EBP-δ, EGR-1, NF-κB, and MIF) are involved in the events of hypoxia-induced lymphangiogenesis. Among them, HIF-1α is known to be the master regulator of cellular oxygen homeostasis, mediating transcriptional activation of lymphangiogenesis via regulation of signaling cascades like VEGF-A/-C/-D, TGF-β and Prox-1 in experimental and human tumors. Although the underlying molecular mechanisms remain incompletely elucidated, the investigation of lymphangiogenesis in hypoxic conditions may provide insight into potential therapeutic targets for lymphatic metastasis.
Cardiac lymphangiogenesis plays an important physiological role in the regulation of interstitial fluid homeostasis, inflammatory, and immune responses. Impaired or excessive cardiac lymphatic ...remodeling and insufficient lymph drainage have been implicated in several cardiovascular diseases including atherosclerosis and myocardial infarction (MI). Although the molecular mechanisms underlying the regulation of functional lymphatics are not fully understood, the interplay between lymphangiogenesis and immune regulation has recently been explored in relation to the initiation and development of these diseases. In this field, experimental therapeutic strategies targeting lymphangiogenesis have shown promise by reducing myocardial inflammation, edema and fibrosis, and improving cardiac function. On the other hand, however, whether lymphangiogenesis is beneficial or detrimental to cardiac transplant survival remains controversial. In the light of recent evidence, cardiac lymphangiogenesis, a thriving and challenging field has been summarized and discussed, which may improve our knowledge in the pathogenesis of cardiovascular diseases and transplant biology.
The lymphatic system provides important functions for tissue fluid homeostasis and immune response. Lymphangiogenesis, the formation of new lymphatics, comprises a series of complex cellular events ...in vitro or in vivo, e.g., proliferation, differentiation, and sprouting. Recent evidence has implied that macrophages act as a direct structural contributor to lymphatic endothelial walls or secret VEGF-C/-D and VEGF-A to initiate lymphangiogenesis in inflamed or tumor tissues. Bone marrow-derived macrophages are versatile cells that express different functional programs in response to exposure to microenvironmental signals, and can be identified by specific expression of a number of proteins, F4/80, CD11b, and CD68. Several causative factors, e.g., NF-κB, IL-1β, TNF-α, SDF-1, M-CSF, especially TonEBP/VEGF-C signaling, may be actively involved in macrophage-induced lymphangiogenesis. Alteration of macrophage phenotype and function has a profound effect on the development and progression of inflammation and malignancy, and macrophage depletion for controlling lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic-associated diseases.
The lymphatic vessels have been implicated in maintenance of interstitial fluid homeostasis and immune responses, and pathological conditions including inflammation, wound healing, lymphedema and ...tumor progression. The knowledge about the lymphatic structure and function in muscles, especially in muscular disorders, remains fragmentary and elusive. LYVE-1-positive initial lymphatics are generally found around skeletal muscle fibers, but not distributed in a fiber type-specific manner. Recent advances in lymphatic research have identified that exercise stimuli trigger adaptive changes in the behavior of initial lymphatics and upregulate lymphangiogenesis. Increasing evidence has supported that muscle disorders are closely correlated with lymphatic dysfunction, growth and remodeling. During these processes, VEGFR-3 and its ligands VEGF-C and VEGF-D are important regulators of muscular lymphangiogenesis. Further studies are necessary to clarify the structural and molecular plasticity of mammalian muscular lymphatics in response to endurance training and pathological events.
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Lymphatic vessels are actively involved in the recovery process of inflamed tissues. However, the changes in intramuscular lymphatic vessels during inflammation caused by skeletal muscle injury ...remain unclear. Therefore, the purpose of this study was to clarify the changes in lymphatic vessels after skeletal muscle injury. The left tibialis anterior muscles of male mice were subjected to lengthening contractions (LC) for inducing skeletal muscle injury, and samples were collected on Days 2, 4, and 7 for examining changes in both the skeletal muscles and intramuscular lymphatic vessels. With hematoxylin–eosin staining, the inflammatory response was observed in myofibers on Days 2 and 4 after LC, whereas regeneration of myofibers was found on Day 7 after LC. The number and area of intramuscular lymphatic vessels analyzed by immunohistochemical staining with an antibody against lymphatic vessel endothelial hyaluronan receptor 1 were significantly increased only on Day 4 after LC. Based on the abovementioned results, intramuscular lymphatic vessels undergo morphological changes such as increase under the state of muscle inflammation. This study demonstrated that the morphology of intramuscular lymphatic vessels undergoes significant changes during the initial recovery phase following skeletal muscle injury.
Lymphatic metastasis of tumor cells represents a series of extremely complex and sequential processes that include dissemination and invasion into surrounding stromal tissues from primary tumors, ...penetration into lymphatic walls and implantation in regional lymph nodes, and extravasation or proliferation in parenchyma of target organs. Recent developments in lymphatic biology and research, especially the application of unique molecular markers specific for lymphatic endothelial cells (LECs), LYVE-1, Prox-1 and podoplanin have provided exciting new insights into the tumor microenvironment and LEC-tumor cell interface. To date, established factors for determining the behavior and prognosis of primary tumors have been emphasized morphologically and physiologically, i.e., lymphatic impairment and vessel density, dysfunction of lymphatic valves, interstitial fluid pressure, as well as a series of lymphangiogenic growth factors including VEGF-C/-D, and other cytokines and chemokines. Increasing knowledge of the tumor biological significance in lymphatics within the tumors (intratumoral lymphatics, ITLs) and at the tumor periphery (peritumoral lymphatics, PTLs) has greatly promoted understanding of tumor access into the lymphatic system by inducing lymphangiogenesis or by co-opting preexisting lymphatics. Therefore, the targeting PTLs and ITLs, which have been proposed as an important route for antimetastatic approach, are deemed worthy of further study in various animal tumor models and human tumors.
Neritidae is one of the most diverse families of Neritimorpha and possesses euryhaline properties. Members of this family usually live on tropical and subtropical coasts and are mainly gregarious. ...The phylogenetic relationships between several subclasses of Gastropoda have been controversial for many years. With an increase in the number of described species of Neritidae, the knowledge of the evolutionary relationships in this family has improved. In the present study, we sequenced four complete mitochondrial genomes from two genera (Clithon and Nerita) and compared them with available complete mitochondrial genomes of Neritidae. Gene order exhibited a highly conserved pattern among three genera in the Neritidae family. Our results improved the phylogenetic resolution within Neritidae, and more comprehensive taxonomic sampling of subclass Neritimorpha was proposed. Furthermore, we reconstructed the divergence among the main lineages of 19 Neritimorpha taxa under an uncorrelated relaxed molecular clock.
To improve the systematics and taxonomy of Patellogastropoda within the evolution of gastropods, we determined the complete mitochondrial genome sequences of Lottia goshimai and Nipponacmea ...fuscoviridis in the family Lottiidae, which presented sizes of 18,192 bp and 18,720 bp, respectively. In addition to 37 common genes among metazoa, we observed duplication of the trnM gene in L. goshimai and the trnM and trnW genes in N. fuscoviridis. The highest A + T contents of the two species were found within protein-coding genes (59.95% and 54.55%), followed by rRNAs (56.50% and 52.44%) and tRNAs (56.42% and 52.41%). trnS1 and trnS2 could not form the canonical cloverleaf secondary structure due to the lack of a dihydrouracil arm in both species. The gene arrangements in all Patellogastropoda compared with those of ancestral gastropods showed different levels of gene rearrangement, including the shuffling, translocation and inversion of single genes or gene fragments. This kind of irregular rearrangement is particularly obvious in the Lottiidae family. The results of phylogenetic and gene rearrangement analyses showed that L. goshimai and Lottia digitalis clustered into one group, which in turn clustered with N. fuscoviridis in Patellogastropoda. This study demonstrates the significance of complete mitogenomes for phylogenetic analysis and enhances our understanding of the evolution of Patellogastropoda.
Blood-brain barrier (BBB) disruption and neuroinflammation are considered key mechanisms of pathogenic Escherichia coli invasion of the brain. However, the specific molecules involved in meningitic ...E. coli-induced BBB breakdown and neuroinflammatory response remain unclear. Our previous RNA-sequencing data from human brain microvascular endothelial cells (hBMECs) revealed two important host factors: platelet-derived growth factor-B (PDGF-B) and intercellular adhesion molecule-1 (ICAM-1), which were significantly upregulated in hBMECs after meningitic E. coli infection. Whether and how PDGF-B and ICAM-1 contribute to the development of E. coli meningitis are still unclear.
The western blot, real-time PCR, enzyme-linked immunosorbent assay, immunohistochemistry, and immunofluorescence were applied to verify the significant induction of PDGF-B and ICAM-1 by meningitic E. coli in vivo and in vitro. Evan's blue assay and electric cell-substrate impedance sensing assay were combined to identify the effects of PDGF-B on BBB permeability. The CRISPR/Cas9 technology, cell-cell adhesion assay, and electrochemiluminescence assay were used to investigate the role of ICAM-1 in neuroinflammation subversion.
We verified the significant induction of PDGF-B and ICAM-1 by meningitic E. coli in mouse as well as monolayer hBMECs models. Functionally, we showed that the increase of PDGF-B may directly enhance the BBB permeability by decreasing the expression of tight junction proteins, and the upregulation of ICAM-1 contributed to neutrophils or monocytes recruitment as well as neuroinflammation subversion in response to meningitic E. coli infection.
Our findings demonstrated the roles of PDGF-B and ICAM-1 in mediating bacterial-induced BBB damage as well as neuroinflammation, providing new concepts and potential targets for future prevention and treatment of bacterial meningitis.
Introduction/Aims
Lymphatic vessels are responsible for the removal of metabolic waste from body tissues. They also play a crucial role in skeletal muscle functioning thorough their high‐energy ...metabolism. In this study we investigated whether disuse muscle atrophy induced by hindlimb unloading is associated with an alteration in the number of lymphatic vessels and differential expression of lymphangiogenic factors in the soleus muscle.
Methods
Male C57BL/6 mice were subjected to tail suspension (TS) for 2 or 4 weeks to induce soleus muscle atrophy. After TS, lymphatic and blood capillaries in the soleus muscle were visualized and counted by double staining with LYVE‐1 and CD31. The protein and mRNA levels of vascular endothelial growth factor (VEGF)‐C, VEGF‐D, and vascular endothelial growth factor receptor‐3 were measured by Western blotting and real‐time reverse transcript polymerase chain reaction, respectively.
Results
TS for 2 weeks resulted in a significant decrease in the number of blood capillaries compared with controls. However, there was no significant change in the number of lymphatic capillaries. By contrast, TS for 4 weeks resulted in a significant decrease in the number of lymphatic and blood capillaries. We observed a significant decrease in the mRNA levels of VEGF‐C and VEGF‐D in mice subjected to TS for 4 weeks.
Discussion
The decrease of intramuscular lymphatic vessels may a crucial role in the process of muscle atrophy.
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