Mechanosensitivity of Jagged-Notch signaling can induce a switch-type behavior in vascular homeostasis

Sandra Loerakker, Oscar Stassen, Fleur M. ter Huurne, Marcelo Boareto, Carlijn V. C. Bouten, Cecilia Sahlgren

Research output: Contribution to journalArticleScientificpeer-review

11 Citations (Scopus)

Abstract

Hemodynamic forces and Notch signaling are both known as key regulators of arterial remodeling and homeostasis. However, how these two factors integrate in vascular morphogenesis and homeostasis is unclear. Here, we combined experiments and modeling to evaluate the impact of the integration of mechanics and Notch signaling on vascular homeostasis. Vascular smooth muscle cells (VSMCs) were cyclically stretched on flexible membranes, as quantified via video tracking, demonstrating that the expression of Jagged1, Notch3, and target genes was down-regulated with strain. The data were incorporated in a computational framework of Notch signaling in the vascular wall, where the mechanical load was defined by the vascular geometry and blood pressure. Upon increasing wall thickness, the model predicted a switch-type behavior of the Notch signaling state with a steep transition of synthetic toward contractile VSMCs at a certain transition thickness. These thicknesses varied per investigated arterial location and were in good agreement with human anatomical data, thereby suggesting that the Notch response to hemodynamics plays an important role in the establishment of vascular homeostasis.
Original languageUndefined/Unknown
Pages (from-to)E3682–E3691
Number of pages10
JournalProceedings of the National Academy of Sciences
Volume115
Issue number16
DOIs
Publication statusPublished - 2018
MoE publication typeA1 Journal article-refereed

Keywords

  • mechanosensitivity
  • Jagged
  • homeostasis
  • Notch

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