Plasticity of Blood- and Lymphatic Endothelial Cells and Marker Identification

Keuschnigg, Johannes; Karinen, Sirkku; Auvinen, Kaisa; Irjala, Heikki; Mpindi, John-Patrick; Kallioniemi, Olli; Hautaniemi, Sampsa; Jalkanen, Sirpa; Salmi, Marko

doi:10.1371/journal.pone.0074293

Cited by 23 publications

(24 citation statements)

References 51 publications

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“…Knockdown of LGALS1 was associated with reduced CEACAM-1 immunofluorescence and loss of cells with high LYVE1 immunofluorescence (these being LEC markers), whereas the immunofluorescent signal for the VEGFR2 coreceptor CD146, which is more abundant in BECs than LECs (fig. S11E) (62,63), was increased ( Fig. 8D and fig.…”

Section: Identification Of Genes Involved In Lec Migration Enables Comentioning

confidence: 90%

Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling

et al. 2017

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Lymphatic vessels constitute a specialized vasculature that is involved in development, cancer, obesity, and immune regulation. The migration of lymphatic endothelial cells (LECs) is critical for vessel growth (lymphangiogenesis) and vessel remodeling, processes that modify the lymphatic network in response to developmental or pathological demands. Using the publicly accessible results of our genome-wide siRNA screen, we characterized the migratome of primary human LECs and identified individual genes and signaling pathways that regulate LEC migration. We compared our data set with mRNA differential expression data from endothelial and stromal cells derived from two in vivo models of lymphatic vessel remodeling, viral infection and contact hypersensitivity-induced inflammation, which identified genes selectively involved in regulating LEC migration and remodeling. We also characterized the top candidates in the LEC migratome in primary blood vascular endothelial cells to identify genes with functions common to lymphatic and blood vascular endothelium. On the basis of these analyses, we showed that , which encodes the glycan-binding protein Galectin-1, promoted lymphatic vascular growth in vitro and in vivo and contributed to maintenance of the lymphatic endothelial phenotype. Our results provide insight into the signaling networks that control lymphangiogenesis and lymphatic remodeling and potentially identify therapeutic targets and biomarkers in disease specific to lymphatic or blood vessels.

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Section: Identification Of Genes Involved In Lec Migration Enables Comentioning

confidence: 90%

Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling

et al. 2017

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“…3B). Noteworthy, when mined from a large EC database [23] cultured LECs expressed higher levels of adenosine receptor ADORA1, similar levels of ADORA2b, and slightly lower levels of ADORA3 than cultured BECs. Moreover, our dermal LECs were not generally unresponsive to all stimuli, since they readily upregulated E-selectin upon in vitro stimulation with TNF-α (data not shown).…”

Section: Adenine Nucleotides and Adenosine Control Leakiness In Humanmentioning

confidence: 99%

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

et al. 2014

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CD73/ecto-5 -nucleotidase is a key enzyme in the regulation of purinergic signaling and inflammatory reactions. It hydrolyzes extracellular AMP into adenosine, which dampens immune cell activation, and reduces leukocyte trafficking. By comparing CD73 expression and function in mononuclear and endothelial cells (ECs) of blood and lymph, we show that extracellular purines and CD73 activity have differential effects in these two vascular systems. We found that CD8-positive T lymphocytes and CD19-positive B lymphocytes in human lymph expressed high levels of CD73 and other purinergic enzymes and adenosine receptors. Soluble CD73 was less abundant in human lymph than in serum, whereas CD73 activity was higher in afferent lymphatic ECs than in blood ECs. Adenosine signaling improved barrier function and induced sprouting of human blood, but not lymphatic, ECs in vitro. Similarly, using CD73-deficient mice we found that CD73 controls only blood vascular permeability at selected lymphoid organs under physiological conditions. Thus, both vascular and lymphatic arms of the immune system synthesize the components of purinergic signaling system, but surprisingly they use CD73 differentially to control endothelial permeability and sprouting.Keywords: adenosine r endothelial cells r lymphatics r permeability r purinergic signaling See accompanying Commentary by Sidibé and Imhof.Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPurinergic signaling plays a central role in controlling inflammation [1][2][3][4][5][6][7]. ATP and other purines are released to the cell Correspondence: Dr. Marko Salmi e-mail: marko.salmi@utu.fi exterior from intracellular pools both under physiological and pathological conditions via diverse pathways including exocytosis, specific channels, transporters, as well as cell death. On the cell surface extracellular ATP is sequentially hydrolyzed to ADP, AMP, * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 562-573 Molecular immunology 563 and adenosine through the action of specific ectonucleotidases [5]. Each of these purines can then bind to specific cell surface receptors and trigger intracellular signaling responses. Notably, ATP and ADP are proinflammatory and prothrombotic molecules, whereas adenosine usually exerts strong anti-inflammatory effects [4]. One rate-limiting enzyme in the purinergic signaling cascade is CD73/ecto-5 -nucleotidase, which converts AMP into adenosine [8,9]. CD73 is expressed on small subsets of lymphocytes, most notably on Treg cells, where it is crucial for the immunesuppressing functions [10]. CD73 is also present on endothelial cells (ECs). It is synthesized both on blood ECs (BECs) and lymphatic ECs (LECs). The role of CD73 on BECs in controlling vascular permeability and leukocyte trafficking is relatively well understood [11][12][13][14][15][16][17], but the function of lymphatic CD73 remains co...

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“…To validate the endothelial nature of HDMEC model in more detail, the expression of pan‐EC markers: CD31/PECAM‐1, vWF, and CD144/VE‐cadherin; and LEC markers: Prox‐1 and Lyve‐1 was investigated by immunofluorescence . HDMEC confluent monolayers showed a positive staining for CD31, vWF, and CD144 (Figure A, panels a‐c).…”

Section: Resultsmentioning

confidence: 85%

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

et al. 2019

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Objective Determine the effect of bradykinin on solute permeability and cellular junctional proteins in human dermis microvascular endothelial cells. Methods Cells were characterized by immunofluorescence and fluorescence‐activated cell sorting. Macromolecular transport of dextran and albumin was monitored. Junctional protein expression and phosphorylation were determined by immunoblot analyses. Intracellular calcium and cAMP levels were evaluated. Target gene expression at mRNA and protein levels was determined. Results Human dermis microvascular endothelial cells comprised 97% lymphatic endothelial cells. Bradykinin increased the permeability to dextran in a concentration‐dependent manner, while reduced the permeability to albumin. Bradykinin treatment down‐regulated VE‐cadherin expression and affected its phosphorylation status at Tyr731. It also down‐regulated claudin‐5 expression at the transcriptional level through bradykinin‐2‐receptor signaling. An increase in the intracellular calcium levels and a reduction in the cAMP concentration were associated effects. Finally, bradykinin induced the up‐regulation of vascular endothelial growth factor‐C protein which was found increased in BK‐induced human dermis microvascular endothelial cells culture supernates. Conclusions Human dermis microvascular endothelial cells represent a model of lymphatic endothelial cells, in which bradykinin‐2‐receptor is expressed. Bradykinin‐induced bradykinin‐2‐receptor signaling through intracellular calcium mobilization and reduction in cAMP levels, triggered changes in solute permeability and cellular junction expression. It further up‐regulated vascular endothelial growth factors‐C protein expression, which is a key modulator of lymphatic vessels function and lymphangiogenesis.

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Plasticity of Blood- and Lymphatic Endothelial Cells and Marker Identification

Cited by 23 publications

References 51 publications

Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling

Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

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