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Frye, Maike
Publications (4 of 4) Show all publications
Zhang, Y., Ulvmar, M. H., Stanczuk, L., Martinez-Corral, I., Frye, M., Alitalo, K. & Mäkinen, T. (2018). Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms. Nature Communications, 9(1), Article ID 1296.
Open this publication in new window or tab >>Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1, article id 1296Article in journal (Refereed) Published
Abstract [en]

Incomplete delivery to the target cells is an obstacle for successful gene therapy approaches. Here we show unexpected effects of incomplete targeting, by demonstrating how heterogeneous inhibition of a growth promoting signaling pathway promotes tissue hyperplasia. We studied the function of the lymphangiogenic VEGFR3 receptor during embryonic and post-natal development. Inducible genetic deletion of Vegfr3 in lymphatic endothelial cells (LECs) leads to selection of non-targeted VEGFR3+cells at vessel tips, indicating an indispensable cell-autonomous function in migrating tip cells. Although Vegfr3 deletion results in lymphatic hypoplasia in mouse embryos, incomplete deletion during post-natal development instead causes excessive lymphangiogenesis. Analysis of mosaically targeted endothelium shows that VEGFR3-LECs non-cell-autonomously drive abnormal vessel anastomosis and hyperplasia by inducing proliferation of non-targeted VEGFR3+LECs through cell-contact-dependent reduction of Notch signaling. Heterogeneity in VEGFR3 levels thus drives vessel hyperplasia, which has implications for the understanding of mechanisms of developmental and pathological tissue growth.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-348896 (URN)10.1038/s41467-018-03692-0 (DOI)000429003400001 ()29615616 (PubMedID)
Funder
Swedish Research Council, 542-2014-3535EU, European Research Council, ERC-2014-CoG-646849Knut and Alice Wallenberg Foundation, 2015.0030Stiftelsen G A Johanssons Minnesfond
Available from: 2018-04-18 Created: 2018-04-18 Last updated: 2018-06-13Bibliographically approved
Frye, M., Taddei, A., Dierkes, C., Martinez-Corral, I., Fielden, M., Ortsäter, H., . . . Mäkinen, T. (2018). Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Nature Communications, 9, Article ID 1511.
Open this publication in new window or tab >>Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 1511Article in journal (Refereed) Published
Abstract [en]

Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-352466 (URN)10.1038/s41467-018-03959-6 (DOI)000430196200006 ()29666442 (PubMedID)
Funder
Swedish Research Council, D0368601]Swedish Research Council, 542-2014-3535]Swedish Cancer Society, CAN 2013/387EU, European Research Council, ERC-2014-CoG-646849Wellcome trust, FC001057
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-06-07Bibliographically approved
Martinez-Corral, I., Stanczuk, L., Frye, M., Ulvmar, M. H., Diegez-Hurtado, R., Olmeda, D., . . . Ortega, S. (2016). Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system. Angiogenesis, 19(3), 433-445
Open this publication in new window or tab >>Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system
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2016 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 19, no 3, p. 433-445Article in journal (Refereed) Published
Abstract [en]

The lymphatic system is essential in many physiological and pathological processes. Still, much remains to be known about the molecular mechanisms that control its development and function and how to modulate them therapeutically. The study of these mechanisms will benefit from better controlled genetic mouse models targeting specifically lymphatic endothelial cells. Among the genes expressed predominantly in lymphatic endothelium, Vegfr3 was the first one identified and is still considered to be one of the best lymphatic markers and a key regulator of the lymphatic system. Here, we report the generation of a Vegfr3-CreER (T2) knockin mouse by gene targeting in embryonic stem cells. This mouse expresses the tamoxifen-inducible CreER(T2) recombinase under the endogenous transcriptional control of the Vegfr3 gene without altering its physiological expression or regulation. The Vegfr3-CreER (T2) allele drives efficient recombination of floxed sequences upon tamoxifen administration specifically in Vegfr3-expressing cells, both in vitro, in primary lymphatic endothelial cells, and in vivo, at different stages of mouse embryonic development and postnatal life. Thus, our Vegfr3-CreER (T2) mouse constitutes a new powerful genetic tool for lineage tracing analysis and for conditional gene manipulation in the lymphatic endothelium that will contribute to improve our current understanding of this system.

National Category
Cardiac and Cardiovascular Systems
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-288518 (URN)10.1007/s10456-016-9505-x (DOI)000379219600013 ()26993803 (PubMedID)
Funder
Swedish Research CouncilEU, European Research Council, ERC-2014-CoG 646849
Note

Erratum in: Angiogenesis 19(3) p. 447 DOI: 10.1007/s10456-016-9518-5

Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2017-11-30Bibliographically approved
Karpyak, V., Biernacka, J., Geske, J., Jenkins, G., Cunningham, J., Rueegg, J., . . . Choi, D. (2015). CLINICAL AND GENETIC MARKERS ASSOCIATED WITH THE LENGTH OF SOBRIETY IN HUMAN ALCOHOLICS TREATED WITH ACAMPROSATE. Paper presented at 38th Annual Scientific Meeting of the Research-Society-on-Alcoholism, JUN 20-24, 2015, San Antonio, TX. Alcoholism: Clinical and Experimental Research, 39, 295A-295A
Open this publication in new window or tab >>CLINICAL AND GENETIC MARKERS ASSOCIATED WITH THE LENGTH OF SOBRIETY IN HUMAN ALCOHOLICS TREATED WITH ACAMPROSATE
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2015 (English)In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 39, p. 295A-295AArticle in journal, Meeting abstract (Other academic) Published
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-266164 (URN)000361637102067 ()
Conference
38th Annual Scientific Meeting of the Research-Society-on-Alcoholism, JUN 20-24, 2015, San Antonio, TX
Available from: 2015-11-10 Created: 2015-11-05 Last updated: 2018-01-10Bibliographically approved
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