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Claesson-Welsh, LenaORCID iD iconorcid.org/0000-0003-4275-2000
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Publications (10 of 116) Show all publications
Georgieva, P. B., Marchuk, D. A., Gerhardt, H., Franco, C. A., Eichmann, A., Claesson-Welsh, L., . . . Oh, P. S. (2019). ATTRACT Arterial Flow as Attractor for Endothelial Cell Migration. Circulation Research, 125(3), 262-264
Open this publication in new window or tab >>ATTRACT Arterial Flow as Attractor for Endothelial Cell Migration
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2019 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 125, no 3, p. 262-264Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2019
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-390423 (URN)10.1161/CIRCRESAHA.119.315198 (DOI)000475949200004 ()31318652 (PubMedID)
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Corada, M., Orsenigo, F., Bhat, G. P., Conze, L. L., Breviario, F., Cunha, S. I., . . . Dejana, E. (2019). Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier. Circulation Research, 124(4), 511-525
Open this publication in new window or tab >>Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier
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2019 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, no 4, p. 511-525Article in journal (Refereed) Published
Abstract [en]

Rationale: The microvasculature of the central nervous system includes the blood-brain barrier (BBB), which regulates the permeability to nutrients and restricts the passage of toxic agents and inflammatory cells. Canonical Wnt/β-catenin signaling is responsible for the early phases of brain vascularization and BBB differentiation. However, this signal declines after birth, and other signaling pathways able to maintain barrier integrity at postnatal stage are still unknown.

Objective: Sox17 (SRY [sex-determining region Y]-box 17) constitutes a major downstream target of Wnt/β-catenin in endothelial cells and regulates arterial differentiation. In the present article, we asked whether Sox17 may act downstream of Wnt/β-catenin in inducing BBB differentiation and maintenance.

Methods and Results: Using reporter mice and nuclear staining of Sox17 and β-catenin, we report that although β-catenin signaling declines after birth, Sox17 activation increases and remains high in the adult. Endothelial-specific inactivation of Sox17 leads to increase of permeability of the brain microcirculation. The severity of this effect depends on the degree of BBB maturation: it is strong in the embryo and progressively declines after birth. In search of Sox17 mechanism of action, RNA sequencing analysis of gene expression of brain endothelial cells has identified members of the Wnt/β-catenin signaling pathway as downstream targets of Sox17. Consistently, we found that Sox17 is a positive inducer of Wnt/β-catenin signaling, and it acts in concert with this pathway to induce and maintain BBB properties. In vivo, inhibition of the β-catenin destruction complex or expression of a degradation-resistant β-catenin mutant, prevent the increase in permeability and retina vascular malformations observed in the absence of Sox17.

Conclusions: Our data highlight a novel role for Sox17 in the induction and maintenance of the BBB, and they underline the strict reciprocal tuning of this transcription factor and Wnt/β-catenin pathway. Modulation of Sox17 activity may be relevant to control BBB permeability in pathological conditions.

Keywords
blood-brain barrier, endothelial cells, permeability, stroke, Wnt/beta-catenin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-378993 (URN)10.1161/CIRCRESAHA.118.313316 (DOI)000458887600025 ()30591003 (PubMedID)
Funder
EU, European Research Council, 742922Swedish Research CouncilKnut and Alice Wallenberg FoundationGerman Research Foundation (DFG), FOR2325
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-03-19Bibliographically approved
Claesson-Welsh, L. (2019). What is normal?: Apelin and VEGFA, drivers of tumor vessel abnormality. EMBO Molecular Medicine, 11(8), Article ID e10892.
Open this publication in new window or tab >>What is normal?: Apelin and VEGFA, drivers of tumor vessel abnormality
2019 (English)In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 11, no 8, article id e10892Article in journal, Editorial material (Other academic) Published
Abstract [en]

In this issue of EMBO Molecular Medicine, Uribesalgo and coworkers show that high Apelin expression correlates with poor survival in advanced breast (MMTV-NeuT) and lung (KRAS(G12D)) murine tumor models as well as in breast and lung cancer in humans. Combining Apelin inhibition (genetically or using an inactive Apelin agonist) with anti-angiogenic therapy using different small molecular weight kinase inhibitors (sunitinib, axitinib) led to marked delay in breast cancer growth in mice. The vasculature in Apelin-targeted cancer showed normalized features including improved perfusion and reduced leakage. These important data provide a strong incentive to target Apelin in human cancer treatment.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-393606 (URN)10.15252/emmm.201910892 (DOI)000479109400007 ()31318171 (PubMedID)
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved
Claesson-Welsh, L. (2018). Alk1 (Activin Receptor-Like Kinase 1) and Vascular Hyperpermeability in Diabetic Retinopathy: More Is Less. Arteriosclerosis, Thrombosis and Vascular Biology, 38(8), 1673-1675
Open this publication in new window or tab >>Alk1 (Activin Receptor-Like Kinase 1) and Vascular Hyperpermeability in Diabetic Retinopathy: More Is Less
2018 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 8, p. 1673-1675Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018
Keywords
Editorials, adherens junctions, blood-brain barrier, diabetic retinopathy, endothelial cells, macular edema
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-366453 (URN)10.1161/ATVBAHA.118.311365 (DOI)000439942200004 ()
Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2018-11-22Bibliographically approved
Sainz-Jaspeado, M. & Claesson-Welsh, L. (2018). Cytokines regulating lymphangiogenesis. Current Opinion in Immunology, 53, 58-63
Open this publication in new window or tab >>Cytokines regulating lymphangiogenesis
2018 (English)In: Current Opinion in Immunology, ISSN 0952-7915, E-ISSN 1879-0372, Vol. 53, p. 58-63Article, review/survey (Refereed) Published
Abstract [en]

Lymphatic vessels are established by differentiation of lymphendothelial progenitors during embryogenesis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing ones is rare in the healthy adult but takes place during pathological conditions such as inflammation, tissue repair and tumor growth. Conditions of dysfunctional lymphatics exist after surgical interventions or in certain genetic diseases. A key lymphangiogenic stimulator is vascular endothelial growth factor-C (VEGFC) acting on VEGF receptor-3 (VEGFR3) expressed on lymphendothelial cells. Other cytokines may act directly to regulate lymphangiogenesis positively or negatively, or indirectly by inducing expression of VEGFC. This review describes different known lymphangiogenic cytokines, their mechanism of action and role in lymphangiogenesis in health and disease.

Place, publisher, year, edition, pages
CURRENT BIOLOGY LTD, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-370056 (URN)10.1016/j.coi.2018.04.003 (DOI)000448096600011 ()29680577 (PubMedID)
Funder
Swedish Research Council, 2015-02375_3Knut and Alice Wallenberg FoundationSwedish Cancer Society, 16 0585
Available from: 2018-12-20 Created: 2018-12-20 Last updated: 2018-12-20Bibliographically approved
Honkura, N., Richards, M., Laviña, B., Sainz-Jaspeado, M., Betsholtz, C. & Claesson-Welsh, L. (2018). Intravital imaging-based analysis tools for vessel identification and assessment of concurrent dynamic vascular events. Nature Communications, 9, Article ID 2746.
Open this publication in new window or tab >>Intravital imaging-based analysis tools for vessel identification and assessment of concurrent dynamic vascular events
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2746Article in journal (Refereed) Published
Abstract [en]

The vasculature undergoes changes in diameter, permeability and blood flow in response to specific stimuli. The dynamics and interdependence of these responses in different vessels are largely unknown. Here we report a non-invasive technique to study dynamic events in different vessel categories by multi-photon microscopy and an image analysis tool, RVDM (relative velocity, direction, and morphology) allowing the identification of vessel categories by their red blood cell (RBC) parameters. Moreover, Claudin5 promoter-driven green fluorescent protein (GFP) expression is used to distinguish capillary subtypes. Intradermal injection of vascular endothelial growth factor A (VEGFA) is shown to induce leakage of circulating dextran, with vessel-type-dependent kinetics, from capillaries and venules devoid of GFP expression. VEGFA-induced leakage in capillaries coincides with vessel dilation and reduced flow velocity. Thus, intravital imaging of non-invasive stimulation combined with RVDM analysis allows for recording and quantification of very rapid events in the vasculature.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-361698 (URN)10.1038/s41467-018-04929-8 (DOI)000438683800004 ()30013228 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation, KAW 20150030Swedish Cancer Society
Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2018-09-26Bibliographically approved
Roche, F. P., Pietilä, I., Kaito, H., Sjöström, E. O., Sobotzki, N., Noguer, O., . . . Claesson-Welsh, L. (2018). Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity. Molecular Cancer Therapeutics, 17(9), 1961-1972
Open this publication in new window or tab >>Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity
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2018 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 17, no 9, p. 1961-1972Article in journal (Refereed) Published
Abstract [en]

The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and anti-tumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and co-localization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG treated gliomas displayed decreased numbers of Interleukin-35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control anti-tumor immunity.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-356836 (URN)10.1158/1535-7163.MCT-18-0097 (DOI)000444041300015 ()29945872 (PubMedID)
Funder
Swedish Cancer Society, 16 0585Swedish Cancer Society, 16 0520Swedish Research Council, 2015-02375_3Swedish Research Council, 2016-01085
Note

I. Pietilä and H. Kaito contributed equally to this article.

Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-11-26Bibliographically approved
Mitran, B., Güler, R., Roche, F. P., Lindström, E., Selvaraju, R., Fleetwood, F., . . . Löfblom, J. (2018). Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model. Theranostics, 8(16), 4462-4476
Open this publication in new window or tab >>Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model
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2018 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 8, no 16, p. 4462-4476Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor receptor-2 (VEGFR2) is a key mediator of angiogenesis and therefore a promising therapeutic target in malignancies including glioblastoma multiforme (GBM). Molecular imaging of VEGFR2 expression may enable patient stratification for antiangiogenic therapy. The goal of the current study was to evaluate the capacity of the novel anti-VEGFR2 biparatopic affibody conjugate (Z(VEGFR2)-Bp(2)) for in vivo visualization of VEGFR2 expression in GBM.

Methods: Z(VEGFR2)-Bp(2) coupled to a NODAGA chelator was generated and radiolabeled with indium-111. The VEGFR2-expressing murine endothelial cell line MS1 was used to evaluate in vitro binding specificity and affinity, cellular processing and targeting specificity in mice. Further tumor targeting was studied in vivo in GL261 glioblastoma orthotopic tumors. Experimental imaging was performed.

Results: [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) bound specifically to VEGFR2 (K-D=33 +/- 18 pM). VEGFR2-mediated accumulation was observed in liver, spleen and lungs. The tumor-to-organ ratios 2 h post injection for mice bearing MS1 tumors were approximately 11 for blood, 15 for muscles and 78 for brain. Intracranial GL261 glioblastoma was visualized using SPECT/CT. The activity uptake in tumors was significantly higher than in normal brain tissue. The tumor-to-cerebellum ratios after injection of 4 mu g [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) were significantly higher than the ratios observed for the 40 mu g injected dose and for the non-VEGFR2 binding size-matched conjugate, demonstrating target specificity. Microautoradiography of cryosectioned CNS tissue was in good agreement with the SPECT/CT images.

Conclusion: The anti-VEGFR2 affibody conjugate [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) specifically targeted VEGFR2 in vivo and visualized its expression in a murine GBM orthotopic model. Tumor-to-blood ratios for [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) were higher compared to other VEGFR2 imaging probes. [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) appears to be a promising probe for in vivo noninvasive visualization of tumor angiogenesis in glioblastoma.

Place, publisher, year, edition, pages
IVYSPRING INT PUBL, 2018
Keywords
VEGFR2, affibody molecule, molecular imaging, SPECT, orthotopic glioma model, in vivo
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-365854 (URN)10.7150/thno.24395 (DOI)000444104300013 ()30214632 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 621-2012-5236Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353VINNOVA, 2016-04060VINNOVA, 2017-02015Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Cancer Society, CAN2017/649Swedish Cancer Society, CAN2013/586Swedish Cancer Society, CAN2016/463Swedish Cancer Society, CAN2014/474Swedish Cancer Society, CAN2017/425Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN2016/585
Note

De två första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet

Available from: 2018-11-15 Created: 2018-11-15 Last updated: 2018-11-15Bibliographically approved
Caolo, V., Peacock, H. M., Kasaai, B., Swennen, G., Gordon, E., Claesson-Welsh, L., . . . Jones, E. A. V. (2018). Shear Stress and VE-Cadherin: The Molecular Mechanism of Vascular Fusion. Arteriosclerosis, Thrombosis and Vascular Biology, 38(9), 2174-2183
Open this publication in new window or tab >>Shear Stress and VE-Cadherin: The Molecular Mechanism of Vascular Fusion
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2018 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 9, p. 2174-2183Article in journal (Refereed) Published
Abstract [en]

Objective: Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion.

Approach and Results: We previously showed that both low shear stress and DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion. We, therefore, investigated vascular endothelial-cadherin (VEC) phosphorylation because this is a common downstream target of low shear stress and DAPT treatment. VEC phosphorylation increases after DAPT treatment and decreased shear stress. The increased phosphorylation occurred independent of the cleavage of the Notch intracellular domain. Increasing shear stress rescues hyperfusion by DAPT treatment by causing the association of the phosphatase vascular endothelial-protein tyrosine phosphatase with VEC, counteracting VEC phosphorylation. Finally, Src (proto-oncogene tyrosine-protein kinase Src) inhibition prevents VEC phosphorylation in endothelial cells and can rescue hyperfusion induced by low shear stress and DAPT treatment. Moesin, a VEC target that was previously reported to mediate endothelial cell rearrangement during lumenization, relocalizes to cell membranes in vascular beds undergoing hyperfusion.

Conclusions: This study provides the first evidence that VEC phosphorylation, induced by DAPT treatment and low shear stress, is involved in the process of fusion during vascular remodeling.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2018
Keywords
cadherins, endothelial cells, hemodynamics, notch receptors, vascular fusion, vascular remodeling, yolk sac
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-362103 (URN)10.1161/ATVBAHA.118.310823 (DOI)000442507900021 ()29930007 (PubMedID)
Available from: 2018-10-01 Created: 2018-10-01 Last updated: 2018-10-01Bibliographically approved
Caolo, V., Peacock, H. M., Kasaai, B., Swennen, G., Gordon, E., Claesson-Welsh, L., . . . Jones, E. A. (2018). Shear stress, notch and VE-cadherin: the molecular mechanism of vascular fusion. Paper presented at 5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, APR 20-22, 2018, Vienna, AUSTRIA. Cardiovascular Research, 114, S13-S13
Open this publication in new window or tab >>Shear stress, notch and VE-cadherin: the molecular mechanism of vascular fusion
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2018 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 114, p. S13-S13Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-357490 (URN)000430678500023 ()
Conference
5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, APR 20-22, 2018, Vienna, AUSTRIA
Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-08-23Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-4275-2000

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