Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program

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Frye , M , Taddei , A , Dierkes , C , Martinez-Corral , I , Fielden , M , Ortsäter , H , Kazenwadel , J , Calado , D P , Ostergaard , P , Salminen , M , He , L , Harvey , N L , Kiefer , F & Mäkinen , T 2018 , ' Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program ' , Nature Communications , vol. 9 , 1511 . https://doi.org/10.1038/s41467-018-03959-6

Title: Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program
Author: Frye, Maike; Taddei, Andrea; Dierkes, Cathrin; Martinez-Corral, Ines; Fielden, Matthew; Ortsäter, Henrik; Kazenwadel, Jan; Calado, Dinis P.; Ostergaard, Pia; Salminen, Marjo; He, Liqun; Harvey, Natasha L.; Kiefer, Friedemann; Mäkinen, Taija
Contributor: University of Helsinki, Departments of Faculty of Veterinary Medicine
Date: 2018-04-17
Language: eng
Number of pages: 16
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/234754
Abstract: 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.
Subject: ENDOTHELIAL-CELL PROGENITORS
SIGNALING PATHWAY
VALVE DEVELOPMENT
LAMINAR-FLOW
IN-VIVO
LYMPHANGIOGENESIS
GROWTH
GATA2
MOUSE
VASCULATURE
1182 Biochemistry, cell and molecular biology
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