Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program
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Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. / 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.
In: NAT COMMUN, Vol. 9, No. 1, 17.04.2018, p. 1511.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program
AU - Frye, Maike
AU - Taddei, Andrea
AU - Dierkes, Cathrin
AU - Martinez-Corral, Ines
AU - Fielden, Matthew
AU - Ortsäter, Henrik
AU - Kazenwadel, Jan
AU - Calado, Dinis P
AU - Ostergaard, Pia
AU - Salminen, Marjo
AU - He, Liqun
AU - Harvey, Natasha L
AU - Kiefer, Friedemann
AU - Mäkinen, Taija
PY - 2018/4/17
Y1 - 2018/4/17
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1038/s41467-018-03959-6
DO - 10.1038/s41467-018-03959-6
M3 - SCORING: Journal article
C2 - 29666442
VL - 9
SP - 1511
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -