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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, no 1, 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. Vol. 9, no 1, article id 1511
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-227501DOI: 10.1038/s41467-018-03959-6ISI: 000430196200006PubMedID: 29666442Scopus ID: 2-s2.0-85045756989OAI: oai:DiVA.org:kth-227501DiVA, id: diva2:1206260
Funder
Swedish Research Council, D0368601 542-2014-3535Swedish Cancer Society, CAN 2013/387EU, European Research Council, ERC-2014-CoG-646849
Note

QC 20180516

Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-05-16Bibliographically approved

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Fielden, Matthew

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