Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 16, Pages E3682-E3691Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1715277115
Keywords
mechanosensitivity; Notch; Jagged; homeostasis
Categories
Funding
- European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant [654513]
- European Union's Seventh Framework Programme [604514]
- Netherlands CardioVascular Research Initiative [CVON2012-01]
- Marie Curie Actions (MSCA) [654513] Funding Source: Marie Curie Actions (MSCA)
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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.
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