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

Nat Commun. 2018 Apr 17;9(1):1511. doi: 10.1038/s41467-018-03959-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / genetics
  • Endothelial Cells / physiology
  • Female
  • GATA2 Transcription Factor / genetics
  • GATA2 Transcription Factor / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Gene Knockdown Techniques
  • Humans
  • Lymphangiogenesis / genetics*
  • Lymphatic Vessels / cytology
  • Lymphatic Vessels / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Primary Cell Culture
  • RNA, Small Interfering / metabolism
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism

Substances

  • GATA2 Transcription Factor
  • GATA2 protein, human
  • Gata2 protein, mouse
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor C
  • vascular endothelial growth factor C, mouse
  • FLT4 protein, human
  • Vascular Endothelial Growth Factor Receptor-3