Lymphendothel in terminaler Herzinsuffizienz und nach Herz- und Lungentransplantation

The lymphatic endothelium is relevant for the pathogenesis of various cardiac and pulmonary diseases. However, the knowledge about the functions and role of lymphatic endothelium in the setting of transplantation is very limited. Therefore it was the main focus of this study. The study investigated the changes of lymphatic endothelial phenotype in patients with terminal heart failure and during the time course after heart and lung transplantation. These observations of the lymphatic phenotype are the first of their kind and provide the evidence, that acute allograft rejection after heart and lung transplantation in human patients is associated with significant changes in the phenotype of lymphatic endothelium. To show the exact mechanistic role of lymphatic endothelium in acute organ rejection and to clarify the cause-effect relation between allograft rejection and lymphatic endothelium, the experimental studies involving heterotopic heart transplantation in rat and mouse were conducted. The results demonstrated that ischemiareperfusion injury induced the activation of lymphatic endothelial cells in rat cardiac allografts. The process was mediated by interaction in the VEGF-C-VEGFR-3 axis and had direct consequences for the development of alloimmune responses. Further, specific perioperative single-dose VEGF-C inhibiting strategies demonstrated beneficial effects on lymphatic vessel activation, antigenpresenting cell trafficking and subsequent development of alloimmune responses in rat cardiac allografts. VEGF-C/D trapping in donor heart prevented acute lymphatic vessel activation and led to homing of VEGFR-3+ dendritic cells in cardiac allograft. Intracoronary ex-vivo perfusion with VEGFC/D trap also improved rat cardiac allograft survival and inhibited the development of cardiac fibrosis, allograft vasculopathy and inflammation. The results of the study, thus, demonstrate the significance of VEGF-C-VEGFR-3 signaling in alloimmunity and suggest VEGF-C/D inhibiting strategies as an alternative clinically feasible immunomodulatory approach targeting lymphatic vessels

The intestinal lymphatic system: Functions and metabolic implications

The lymphatic system of the gut plays important roles in the transport of dietary lipids, as well as in immunosurveillance and removal of interstitial fluid. Historically, despite its crucial functions in intestinal homeostasis, the lymphatic system has been poorly studied. In the last 2 decades, identification of specific molecular mediators of lymphatic endothelial cells (LECs) growth together with novel genetic approaches and intravital imaging techniques, have advanced our understanding of the mechanisms regulating intestinal lymphatic physiology in health and disease. As its metabolic implications are gaining recognition, intestinal lymphatic biology is currently experiencing a surge in interest. This review describes current knowledge related to molecular control of intestinal lymphatic vessel structure and function. We discuss regulation of chylomicron entry into lymphatic vessels by vascular endothelial growth factors (VEGFs), hormones, transcription factors and the specific signaling pathways involved. The information covered supports the emerging role of intestinal lymphatics in etiology of the metabolic syndrome and their potential as a therapeutic target. Keywords: Lacteals, Lipid, VEGF Signaling, Endothelium, Obesit

Hematopoietic Stem Cells Contribute to Lymphatic Endothelium

Although the lymphatic system arises as an extension of venous vessels in the embryo, little is known about the role of circulating progenitors in the maintenance or development of lymphatic endothelium. Here, we investigated whether hematopoietic stem cells (HSCs) have the potential to give rise to lymphatic endothelial cells (LEC). mice resulted in the incorporation of donor-derived LEC into the lymphatic vessels of spontaneously arising intestinal tumors.Our results indicate that HSCs can contribute to normal and tumor associated lymphatic endothelium. These findings suggest that the modification of HSCs may be a novel approach for targeting tumor metastasis and attenuating diseases of the lymphatic system

Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD

<p>Background De novo lymphatic vessel formation has recently been observed in lungs of patients with moderate chronic obstructive pulmonary disease (COPD). However, the distribution of lymphatic vessel changes among the anatomical compartments of diseased lungs is unknown. Furthermore, information regarding the nature of lymphatic vessel alterations across different stages of COPD is missing. This study performs a detailed morphometric characterization of lymphatic vessels in major peripheral lung compartments of patients with different severities of COPD and investigates the lymphatic expression of molecules involved in immune cell trafficking.</p> <p>Methods Peripheral lung resection samples obtained from patients with mild (GOLD stage I), moderate-severe (GOLD stage II-III), and very severe (GOLD stage IV) COPD were investigated for podoplanin-immunopositive lymphatic vessels in distinct peripheral lung compartments: bronchioles, pulmonary blood vessels and alveolar walls. Control subjects with normal lung function were divided into never smokers and smokers. Lymphatics were analysed by multiple morphological parameters, as well as for their expression of CCL21 and the chemokine scavenger receptor D6.</p> <p>Results The number of lymphatics increased by 133% in the alveolar parenchyma in patients with advanced COPD compared with never-smoking controls (p <0.05). In patchy fibrotic lesions the number of alveolar lymphatics increased 20-fold from non-fibrotic parenchyma in the same COPD patients. The absolute number of lymphatics per bronchiole and artery was increased in advanced COPD, but numbers were not different after normalization to tissue area. Increased numbers of CCL21- and D6-positive lymphatics were observed in the alveolar parenchyma in advanced COPD compared with controls (p <0.01). Lymphatic vessels also displayed increased mean levels of immunoreactivity for CCL21 in the wall of bronchioles (p < 0.01) and bronchiole-associated arteries (p < 0.05), as well as the alveolar parenchyma (p < 0.001) in patients with advanced COPD compared with never-smoking controls. A similar increase in lymphatic D6 immunoreactivity was observed in bronchioles (p <0.05) and alveolar parenchyma (p < 0.01).</p> <p>Conclusions This study shows that severe stages of COPD is associated with increased numbers of alveolar lymphatic vessels and a change in lymphatic vessel phenotype in major peripheral lung compartments. This novel histopathological feature is suggested to have important implications for distal lung immune cell traffic in advanced COPD.</p&gt

The Road Less Traveled: Regulation of Leukocyte Migration Across Vascular and Lymphatic Endothelium by Galectins

Leukocyte entry from the blood into inflamed tissues, exit into the lymphatics, and migration to regional lymph nodes are all crucial processes for mounting an effective adaptive immune response. Leukocytes must cross two endothelial cell layers, the vascular and the lymphatic endothelial cell layers, during the journey from the blood to the lymph node. The proteins and cellular interactions which regulate leukocyte migration across the vascular endothelium are well studied; however, little is known about the factors that regulate leukocyte migration across the lymphatic endothelium. Here, we will summarize evidence for a role for galectins, a family of carbohydrate-binding proteins, in regulating leukocyte migration across the vascular endothelium and propose that galectins are also involved in leukocyte migration across the lymphatic endothelium

Aquaporin-4 Functionality and Virchow-Robin Space Water Dynamics: Physiological Model for Neurovascular Coupling and Glymphatic Flow.

The unique properties of brain capillary endothelium, critical in maintaining the blood-brain barrier (BBB) and restricting water permeability across the BBB, have important consequences on fluid hydrodynamics inside the BBB hereto inadequately recognized. Recent studies indicate that the mechanisms underlying brain water dynamics are distinct from systemic tissue water dynamics. Hydrostatic pressure created by the systolic force of the heart, essential for interstitial circulation and lymphatic flow in systemic circulation, is effectively impeded from propagating into the interstitial fluid inside the BBB by the tightly sealed endothelium of brain capillaries. Instead, fluid dynamics inside the BBB is realized by aquaporin-4 (AQP-4), the water channel that connects astrocyte cytoplasm and extracellular (interstitial) fluid. Brain interstitial fluid dynamics, and therefore AQP-4, are now recognized as essential for two unique functions, namely, neurovascular coupling and glymphatic flow, the brain equivalent of systemic lymphatics

Lymphatic endothelium in health and disease

The lymphatic vascular system has an important role in the maintenance of tissue fluid pressure homeostasis, in the mediation of the afferent immune response via recruitment of antigen-presenting cells toward draining lymph nodes, and in the intestinal absorption of dietary lipids. Substantial progress in our understanding of the development and the molecular mechanisms controlling the lymphatic system has been made during the last few years, based on a recent wave of discoveries of lymphatic endothelial cell-specific markers and growth factors. This has also led to new insights into the role of lymphatic endothelium in a number of diseases, including primary and secondary lymphedemas. The emerging role of lymphatic endothelium in the context of inflammation indicates that therapeutics targeting the lymphatic vasculature might represent a new strategy for anti-inflammatory therapie

High relative density of lymphatic vessels predicts poor survival in tongue squamous cell carcinoma

Tongue cancer has a poor prognosis due to its early metastasis via lymphatic vessels. The present study aimed at evaluating lymphatic vessel density, relative density of lymphatic vessel, and diameter of lymphatic vessels and its predictive role in tongue cancer. Paraffin-embedded tongue and lymph node specimens (n = 113) were stained immunohistochemically with a polyclonal antibody von Willebrand factor, recognizing blood and lymphatic endothelium and with a monoclonal antibody podoplanin, recognizing lymphatic endothelium. The relative density of lymphatic vessels was counted by dividing the mean number of lymphatic vessels per microscopic field (podoplanin) by the mean number of all vessels (vWf) per microscopic field. The high relative density of lymphatic vessels (aeyen80 %) was associated with poor prognosis in tongue cancer. The relative density of lymphatic vessels predicted poor prognosis in the group of primary tumor size T1-T2 and in the group of non-metastatic cancer. The lymphatic vessel density and diameter of lymphatic vessels were not associated with tongue cancer survival. The relative density of lymphatic vessels might have clinically relevant prognostic impact. Further studies with increased number of patients are needed.Peer reviewe

microRNAs in the Lymphatic Endothelium : Master Regulators of Lineage Plasticity and Inflammation

microRNAs (miRNAs) are highly conserved, small non-coding RNAs that regulate gene expression at the posttranscriptional level. They have crucial roles in organismal development, homeostasis, and cellular responses to pathological stress. The lymphatic system is a large vascular network that actively regulates the immune response through antigen trafficking, cytokine secretion, and inducing peripheral tolerance. Here, we review the role of miRNAs in the lymphatic endothelium with a particular focus on their role in lymphatic endothelial cell (LEC) plasticity, inflammation, and regulatory function. We highlight the lineage plasticity of LECs during inflammation and the importance of understanding the regulatory role of miRNAs in these processes. We propose that targeting miRNA expression in lymphatic endothelium can be a novel strategy in treating human pathologies associated with lymphatic dysfunction