Browsing by Subject "VESSELS"

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  • Aspelund, Aleksanteri; Antila, Salli; Proulx, Steven T.; Karlsen, Tine Veronica; Karaman, Sinem; Detmar, Michael; Wiig, Helge; Alitalo, Kari (2015)
    The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.
  • Haegerling, Rene; Pollmann, Cathrin; Andreas, Martin; Schmidt, Christian; Nurmi, Harri; Adams, Ralf H.; Alitalo, Kari; Andresen, Volker; Schulte-Merker, Stefan; Kiefer, Friedemann (2013)
  • Jacob, Laurent; Boisserand, Ligia Simoes Braga; Geraldo, Luiz Henrique Medeiros; Neto, Jose de Brito; Mathivet, Thomas; Antila, Salli; Barka, Besma; Xu, Yunling; Thomas, Jean-Mickael; Pestel, Juliette; Aigrot, Marie-Stephane; Song, Eric; Nurmi, Harri; Lee, Seyoung; Alitalo, Kari; Renier, Nicolas; Eichmann, Anne; Thomas, Jean-Leon (2019)
    Cranial lymphatic vessels (LVs) are involved in the transport of fluids, macromolecules and central nervous system (CNS) immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we show an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO(+)-clarified spine segments. Vertebral LVs connect to peripheral sensory and sympathetic ganglia and form metameric vertebral circuits connecting to lymph nodes and the thoracic duct. They drain the epidural space and the dura mater around the spinal cord and associate with leukocytes. Vertebral LVs remodel extensively after spinal cord injury and VEGF-C-induced vertebral lymphangiogenesis exacerbates the inflammatory responses, T cell infiltration and demyelination following focal spinal cord lesion. Therefore, vertebral LVs add to skull meningeal LVs as gatekeepers of CNS immunity and may be potential targets to improve the maintenance and repair of spinal tissues.
  • Vaahtomeri, Kari; Brown, Markus; Hauschild, Robert; De Vries, Ingrid; Leithner, Alexander Franz; Mehling, Matthias; Kaufmann, Walter Anton; Sixt, Michael (2017)
    Trafficking cells frequently transmigrate through epithelial and endothelial monolayers. How monolayers cooperate with the penetrating cells to support their transit is poorly understood. We studied dendritic cell (DC) entry into lymphatic capillaries as a model system for transendothelial migration. We find that the chemokine CCL21, which is the decisive guidance cue for intravasation, mainly localizes in the trans-Golgi network and intracellular vesicles of lymphatic endothelial cells. Upon DC transmigration, these Golgi deposits disperse and CCL21 becomes extracellularly enriched at the sites of endothelial cell-cell junctions. When we reconstitute the transmigration process in vitro, we find that secretion of CCL21-positive vesicles is triggered by a DC contact-induced calcium signal, and selective calcium chelation in lymphatic endothelium attenuates transmigration. Altogether, our data demonstrate a chemokine-mediated feedback between DCs and lymphatic endothelium, which facilitates transendothelial migration.
  • Houssari, Mahmoud; Dumesnil, Anais; Tardif, Virginie; Kivela, Riikka; Pizzinat, Nathalie; Boukhalfa, Ines; Godefroy, David; Schapman, Damien; Hemanthakumar, Karthik A.; Bizou, Mathilde; Henry, Jean-Paul; Renet, Sylvanie; Riou, Gaetan; Rondeaux, Julie; Anouar, Youssef; Adriouch, Sahil; Fraineau, Sylvain; Alitalo, Kari; Richard, Vincent; Mulder, Paul; Brakenhielm, Ebba (2020)
    Objective: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-C(C156S)therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4(+)and CD8(+)T cells potently suppress, in part through interferon-gamma, cardiac lymphangiogenesis post-MI. Conclusions: We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-C-C156S. Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.
  • Pekkonen, Pirita; Alve, Sanni; Balistreri, Giuseppe; Gramolelli, Silvia; Tatti-Bugaeva, Olga; Paatero, Ilkka; Niiranen, Otso; Tuohinto, Krista; Perala, Nina; Taiwo, Adewale; Zinovkina, Nadezhda; Repo, Pauliina; Icay, Katherine; Ivaska, Joanna; Saharinen, Pipsa; Hautaniemi, Sampsa; Lehti, Kaisa; Ojala, Paivi M. (2018)
    Lymphatic invasion and lymph node metastasis correlate with poor clinical outcome in melanoma. However, the mechanisms of lymphatic dissemination in distant metastasis remain incompletely understood. We show here that exposure of expansively growing human WM852 melanoma cells, but not singly invasive Bowes cells, to lymphatic endothelial cells (LEC) in 3D co-culture facilitates melanoma distant organ metastasis in mice. To dissect the underlying molecular mechanisms, we established LEC co-cultures with different melanoma cells originating from primary tumors or metastases. Notably, the expansively growing metastatic melanoma cells adopted an invasively sprouting phenotype in 3D matrix that was dependent on MMP14, Notch3 and beta 1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident beta 1-integrin activation. Moreover, MMP14 and Notch3 were required for LEC-mediated metastasis of zebrafish xenografts. This study uncovers a unique mechanism whereby LEC contact promotes melanoma metastasis by inducing a reversible switch from 3D growth to invasively sprouting cell phenotype.
  • Brown, Markus; Johnson, Louise A.; Leone, Dario A.; Majek, Peter; Vaahtomeri, Kari; Senfter, Daniel; Bukosza, Nora; Schachner, Helga; Asfour, Gabriele; Langer, Brigitte; Hauschild, Robert; Parapatics, Katja; Hong, Young-Kwon; Bennett, Keiryn L.; Kain, Renate; Detmar, Michael; Sixt, Michael; Jackson, David G.; Kerjaschki, Dontscho (2018)
    Lymphatic endothelial cells (LECs) release extracellular chemokines to guide the migration of dendritic cells. In this study, we report that LECs also release basolateral exosome-rich endothelial vesicles (EEVs) that are secreted in greater numbers in the presence of inflammatory cytokines and accumulate in the perivascular stroma of small lymphatic vessels in human chronic inflammatory diseases. Proteomic analyses of EEV fractions identified >1,700 cargo proteins and revealed a dominant motility-promoting protein signature. In vitro and ex vivo EEV fractions augmented cellular protrusion formation in a CX3CL1/fractalkine-dependent fashion and enhanced the directional migratory response of human dendritic cells along guidance cues. We conclude that perilymphatic LEC exosomes enhance exploratory behavior and thus promote directional migration of CX3CR1-expressing cells in complex tissue environments.
  • Gucciardo, Erika; Loukovaara, Sirpa; Salven, Petri; Lehti, Kaisa (2018)
    Diabetic retinopathy (DR) is the most common diabetic microvascular complication and major cause of blindness in working-age adults. According to the level of microvascular degeneration and ischemic damage, DR is classified into non-proliferative DR (NPDR), and end-stage, proliferative DR (PDR). Despite advances in the disease etiology and pathogenesis, molecular understanding of end-stage PDR, characterized by ischemia- and inflammation-associated neovascularization and fibrosis, remains incomplete due to the limited availability of ideal clinical samples and experimental research models. Since a great portion of patients do not benefit from current treatments, improved therapies are essential. DR is known to be a complex and multifactorial disease featuring the interplay of microvascular, neurodegenerative, metabolic, genetic/epigenetic, immunological, and inflammation-related factors. Particularly, deeper knowledge on the mechanisms and pathophysiology of most advanced PDR is critical. Lymphatic-like vessel formation coupled with abnormal endothelial differentiation and progenitor cell involvement in the neovascularization associated with PDR are novel recent findings which hold potential for improved DR treatment. Understanding the underlying mechanisms of PDR pathogenesis is therefore crucial. To this goal, multidisciplinary approaches and new ex vivo models have been developed for a more comprehensive molecular, cellular and tissue-level understanding of the disease. This is the first step to gain the needed information on how PDR can be better evaluated, stratified, and treated.
  • Nitschke, Maximilian; Bell, Alexander; Karaman, Sinem; Amouzgar, Meelad; Rutkowski, Joseph M.; Scherer, Philipp E.; Alitalo, Kari; McDonald, Donald M. (2017)
    Chylous pleural effusion (chylothorax) frequently accompanies lymphatic vessel malformations and other conditions with lymphatic defects. Although retrograde flow of chyle from the thoracic duct is considered a potential mechanism underlying chylothorax in patients and mouse models, the path chyle takes to reach the thoracic cavity is unclear. Herein, we use a novel transgenic mouse model, where doxycycline-induced overexpression of vascular endothelial growth factor (VEGF)-C was driven by the adipocyte-specific promoter adiponectin (ADN), to determine how chylothorax forms. Surprisingly, 100% of adult ADN-VEGF-C mice developed chylothorax within 7 days. Rapid, consistent appearance of chylothorax enabled us to examine the step-by-step development in otherwise normal adult mice. Dynamic imaging with a fluorescent tracer revealed that lymph in the thoracic duct of these mice could enter the thoracic cavity by retrograde flow into enlarged paravertebral Lymphatics and subpleural lymphatic plexuses that had incompetent Lymphatic valves. Pleural mesothelium overlying the lymphatic plexuses underwent exfoliation that increased during doxycycline exposure. Together, the findings indicate that chylothorax in ADN-VEGF-C mice results from retrograde flow of chyle from the thoracic duct into lymphatic tributaries with defective valves. Chyle extravasates from these plexuses and enters the thoracic cavity through exfoliated regions of the pleural mesothelium.
  • Hujanen, Roosa A M; Almahmoudi, Rabeia; Karinen, Sini; Nwaru, Bright; Salo, Tuula; Salem, Abdelhakim (2020)
    Vasculogenic mimicry (VM) is an intratumoral microcirculation pattern formed by aggressive cancer cells, which mediates tumor growth. In this study, we compiled the evidence from studies evaluating whether positive VM status can serve as a prognostic factor to patients with squamous cell carcinoma of the head and neck (HNSCC) or esophagus (ESCC). Comprehensive systematic searches were conducted using Cochrane Library, Ovid Medline, PubMed, and Scopus databases. We appraised the quality of studies and the potential for bias, and performed random-effect meta-analysis to assess the prognostic impact of VM on the overall survival (OS). Seven studies with 990 patients were eligible, where VM was detected in 34.24% of patients. Positive-VM was strongly associated with poor OS (hazard ratio = 0.50; 95% confidence interval: 0.38-0.64), which remained consistent following the subgroup analysis of the studies. Furthermore, VM was associated with more metastasis to local lymph nodes and more advanced stages of HNSCC and ESCC. In conclusion, this study provides clear evidence showing that VM could serve as a promising prognosticator for patients with either HNSCC or ESCC. Further studies are warranted to assess how VM can be implemented as a reliable staging element in clinical practice and whether it could provide a new target for therapeutic intervention.