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Claesson-Welsh, LenaORCID iD iconorcid.org/0000-0003-4275-2000
Alternative names
Publications (10 of 120) 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
Tisch, N., Freire-Valls, A., Yerbes, R., Paredes, I., La Porta, S., Wang, X., . . . Ruiz de Almodovar, C. (2019). Caspase-8 modulates physiological and pathological angiogenesis during retina development. Journal of Clinical Investigation, 129(12), 5092-5107
Open this publication in new window or tab >>Caspase-8 modulates physiological and pathological angiogenesis during retina development
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2019 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 129, no 12, p. 5092-5107Article in journal (Refereed) Published
Abstract [en]

During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether, how, cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates cell death via both apoptosis and necroptosis. Here, we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal retina angiogenesis. EC-specific Casp-8-KO pups (Casp-8(ECKO)) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting, and migration independently of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 MAPK downstream of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and destabilization of vascular endothelial cadherin (VE-cadherin) at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR) resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs was beneficial, as pathological neovascularization was reduced in Casp-8ECKO pups. Taking these data together, we show that Casp-8 acts in a cell death-independent manner in ECs to regulate the formation of the retina vasculature and that Casp-8 in ECs is mechanistically involved in the pathophysiology of ROP.

Place, publisher, year, edition, pages
AMER SOC CLINICAL INVESTIGATION INC, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-400683 (URN)10.1172/JCI122767 (DOI)000500567600012 ()31454332 (PubMedID)
Funder
EU, European Research Council, ERC-StG-311367
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically 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
Testini, C., Smith, R. O., Jin, Y., Martinsson, P., Sun, Y., Hedlund, M., . . . Claesson-Welsh, L. (2019). Myc-dependent endothelial proliferation is controlled by phosphotyrosine 1212 in VEGF receptor-2. EMBO Reports, 20(11), Article ID e47845.
Open this publication in new window or tab >>Myc-dependent endothelial proliferation is controlled by phosphotyrosine 1212 in VEGF receptor-2
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2019 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 20, no 11, article id e47845Article in journal (Refereed) Published
Abstract [en]

Exaggerated signaling by vascular endothelial growth factor (VEGF)-A and its receptor, VEGFR2, in pathologies results in poor vessel function. Still, pharmacological suppression of VEGFA/VEGFR2 may aggravate disease. Delineating VEGFR2 signaling in vivo provides strategies for suppression of specific VEGFR2-induced pathways. Three VEGFR2 tyrosine residues (Y949, Y1212, and Y1173) induce downstream signaling. Here, we show that knock-in of phenylalanine to create VEGFR2 Y1212F in C57Bl/6 and FVB mouse strains leads to loss of growth factor receptor-bound protein 2- and phosphoinositide 3 '-kinase (PI3K)p85 signaling. C57Bl/6 Vegfr2(Y1212F/Y1212F) show reduced embryonic endothelial cell (EC) proliferation and partial lethality. FVB Vegfr2(Y1212F/Y1212F) show reduced postnatal EC proliferation. Reduced EC proliferation in Vegfr2(Y1212F/Y1212F) explants is rescued by c-Myc overexpression. We conclude that VEGFR2 Y1212 signaling induces activation of extracellular-signal-regulated kinase (ERK)1/2 and Akt pathways required for c-Myc-dependent gene regulation, endothelial proliferation, and vessel stability.

Keywords
angiogenesis, GRB2, Nck, PI3Kp85, proliferation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-397954 (URN)10.15252/embr.201947845 (DOI)000496229500001 ()31545012 (PubMedID)
Funder
Swedish Research Council, 2015-02375Swedish Cancer Society, CAN2016/578Knut and Alice Wallenberg Foundation, KAW 2015.0030Knut and Alice Wallenberg Foundation, 2015.0275
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
Ragunathrao, V. A., Anwar, M., Akhter, M. Z., Chavez, A., Mao, D. Y., Natarajan, V., . . . Mehta, D. (2019). Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling. Cell reports, 29(11), 3472-3487
Open this publication in new window or tab >>Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 29, no 11, p. 3472-3487Article in journal (Refereed) Published
Abstract [en]

The vascular endothelial growth factor-A (VEGF-A)-VEGFR2 pathway drives tumor vascularization by activating proangiogenic signaling in endothelial cells (ECs). Here, we show that EC-sphingosine-1-phosphate receptor 1 (S1PR1) amplifies VEGFR2-mediated angiogenic signaling to enhance tumor growth. We show that cancer cells induce S1 PR1 activity in ECs, and thereby, conditional deletion of Si PR1 in ECs (EC-Slpr1(-/-) mice) impairs tumor vascularization and growth. Mechanistically, we show that S1 PR1 engages the heterotrimeric G-protein Gi, which amplifies VEGF-VEGFR2 signaling due to an increase in the activity of the tyrosine kinase c-Abl1. c-Abl1, by phosphorylating VEGFR2 at tyrosine-951, prolongs VEGFR2 retention on the plasmalemma to sustain Rac1 activity and EC migration. Thus, S1 PR1 or VEGFR2 antagonists, alone or in combination, reverse the tumor growth in control mice to the level seen in EC-Slpr1(-/-) mice. Our findings suggest that blocking S1 PR1 activity in ECs has the potential to suppress tumor growth by preventing amplification of VEGF-VEGFR2 signaling.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-400820 (URN)10.1016/j.celrep.2019.11.036 (DOI)000502113400012 ()31825830 (PubMedID)
Available from: 2020-01-13 Created: 2020-01-13 Last updated: 2020-01-13Bibliographically approved
Pietilä, I., van Mourik, D., Tamelander, A., Kriz, V., Claesson-Welsh, L., Tengholm, A. & Welsh, M. (2019). Temporal Dynamics of VEGFA-Induced VEGFR2/FAK Co-Localization Depend on SHB. Cells, 8(12), Article ID 1645.
Open this publication in new window or tab >>Temporal Dynamics of VEGFA-Induced VEGFR2/FAK Co-Localization Depend on SHB
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2019 (English)In: Cells, ISSN 2073-4409, Vol. 8, no 12, article id 1645Article in journal (Refereed) Published
Abstract [en]

Focal adhesion kinase (FAK) is essential for vascular endothelial growth factor-A (VEGFA)/VEGF receptor-2 (VEGFR2)-stimulated angiogenesis and vascular permeability. We have previously noted that presence of the Src homology-2 domain adapter protein B (SHB) is of relevance for VEGFA-stimulated angiogenesis in a FAK-dependent manner. The current study was conducted in order address the temporal dynamics of co-localization between these components in HEK293 and primary lung endothelial cells (EC) by total internal reflection fluorescence microscopy (TIRF). An early (<2.5 min) VEGFA-induced increase in VEGFR2 co-localization with SHB was dependent on tyrosine 1175 in VEGFR2. VEGFA also enhanced SHB co-localization with FAK. FAK co-localization with VEGFR2 was dependent on SHB since it was significantly lower in SHB deficient EC after VEGFA addition. Absence of SHB also resulted in a gradual decline of VEGFR2 co-localization with FAK under basal (prior to VEGFA addition) conditions. A similar basal response was observed with expression of the Y1175F-VEGFR2 mutant in wild type EC. The distribution of focal adhesions in SHB-deficient EC was altered with a primarily perinuclear location. These live cell data implicate SHB as a key component regulating FAK activity in response to VEGFA/VEGFR2.

Place, publisher, year, edition, pages
Basel, Switzerland: MDPI, 2019
Keywords
VEGFR2, FAK, SHB, TIRF, focal adhesions, angiogenesis
National Category
Basic Medicine Cell Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-400532 (URN)10.3390/cells8121645 (DOI)000506643500173 ()
Funder
Swedish Research CouncilSwedish Cancer SocietyErnfors FoundationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-12-23 Created: 2019-12-23 Last updated: 2020-02-27Bibliographically 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
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ORCID iD: ORCID iD iconorcid.org/0000-0003-4275-2000

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