Computational analysis of the role of mechanosensitive Notch signaling in arterial adaptation to hypertension

Figures

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  Fig. 1. Overview of the methods and processes in the computational framework. (A) Schematic representation of mechanosensitive Notch signaling. Notch receptors of one cell interact with Jagged ligands of an adjacent cell to release NICD which translocates to the nucleus. The expression of Notch3 and Jagged1 is downregulated by mechanical strain. Low strain results in high Notch activity and a contractile phenotype, high strain results in low Notch activity and a synthetic phenotype. (B) Visualization of the kinematics of the simulated coronary artery. (C) Example of the outcome of fitting the model to experimental data of a biaxial tensile test. (D) The circumferential stretch distribution of the arterial wall at normal blood pressure (120/80 mmHg), optimized to be approximately uniform by calibrating the circumferential residual stresses. (E) Releasing the axial residual stresses results in a shortening of the artery in axial direction, consistent with the imposed axial pre-stretch. (F) Releasing the circumferential residual stresses results in the opening of the artery, consistent with the imposed circumferential pre-stretch.

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  Fig. 2. Distributions of the elastic circumferential stretch over the arterial wall for different blood pressure values. (A) mean stretch at normal blood pressure, (B) mean stretch in ISH, (C) mean stretch in IDH, (D) mean stretch in CH, (E) systolic stretch at normal blood pressure, (F) systolic stretch in ISH, (G) systolic stretch in IDH, (H) systolic stretch in CH.

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  Fig. 3. Results of the computational framework for different blood pressure values associated with isolated systolic hypertension. Elastic circumferential stretch distributions over the arterial wall of systolic stretch (A), mean stretch (B), and dynamic stretch (C). Predicted NICD levels of the VSMCs in the arterial wall based on the stretch distributions using systolic stretch (D), mean stretch (E), or dynamic stretch (F) as target variable for mechanosensitive Notch signaling. NICD values are normalized to the situation at normal blood pressure (dashed line). Predicted phenotypes of the VSMCs in the arterial wall based on their NICD content using systolic stretch (G), mean stretch (H), or dynamic stretch (I) as target variable for mechanosensitive Notch signaling. White cells represent homeostatic VSMCs under normal blood pressure, blue cells represent progressively more synthetic VSMCs, and red cells represent progressively more contractile VSMCs. In all figures, the arterial wall runs from the luminal side on the left to the outside on the right.

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  Fig. 4. Results of the computational framework for different blood pressure values associated with isolated diastolic hypertension. Elastic circumferential stretch distributions over the arterial wall of systolic stretch (A), mean stretch (B), and dynamic stretch (C). Predicted NICD levels of the VSMCs in the arterial wall based on the stretch distributions using systolic stretch (D), mean stretch (E), or dynamic stretch (F) as target variable for mechanosensitive Notch signaling. NICD values are normalized to the situation at normal blood pressure (dashed line). Predicted phenotypes of the VSMCs in the arterial wall based on their NICD content using systolic stretch (G), mean stretch (H), or dynamic stretch (I) as target variable for mechanosensitive Notch signaling. White cells represent homeostatic VSMCs under normal blood pressure, blue cells represent progressively more synthetic VSMCs, and red cells represent progressively more contractile VSMCs. In all figures, the arterial wall runs from the luminal side on the left to the outside on the right.

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  Fig. 5. Results of the computational framework for different blood pressure values associated with combined hypertension. Elastic circumferential stretch distributions over the arterial wall of systolic stretch (A), mean stretch (B), and dynamic stretch (C). Predicted NICD levels of the VSMCs in the arterial wall based on the stretch distributions using systolic stretch (D), mean stretch (E), or dynamic stretch (F) as target variable for mechanosensitive Notch signaling. NICD values are normalized to the situation at normal blood pressure (dashed line). Predicted phenotypes of the VSMCs in the arterial wall based on their NICD content using systolic stretch (G), mean stretch (H), or dynamic stretch (I) as target variable for mechanosensitive Notch signaling. White cells represent homeostatic VSMCs under normal blood pressure, blue cells represent progressively more synthetic VSMCs, and red cells represent progressively more contractile VSMCs. In all figures, the arterial wall runs from the luminal side on the left to the outside on the right.

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  Fig. 6. Effects of a loss of residual stress on circumferential stretch, NICD content, and VSMC phenotype. Elastic circumferential stretch distributions over the arterial wall at mean blood pressure for a loss of axial residual stress (A), circumferential residual stress (B), and a combination of both (C). Predicted NICD levels of the VSMCs in the arterial wall for a loss of axial residual stress (D), circumferential residual stress (E), and a combination of both (F). Predicted phenotypes of the VSMCs in the arterial for a loss of axial residual stress (G), circumferential residual stress (H), and a combination of both (I). White cells represent homeostatic VSMCs, blue cells represent progressively more synthetic VSMCs, and red cells represent progressively more contractile VSMCs. The percentages indicate the amount of residual stress present in the material. In all figures, the arterial wall runs from the luminal side on the left to the outside on the right. Percentages indicate the amount of axial and/or circumferential pre-stretch that was lost.

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  Fig. 7. Effects of a loss of residual stress combined with hypertension on circumferential stretch, NICD content, and VSMC phenotype. Elastic circumferential stretch distributions over the arterial wall at mean blood pressure for a loss of axial (A) and circumferential residual stress (B). Predicted NICD levels of the VSMCs in the arterial wall for a loss of axial (C) and circumferential residual stress (D). Predicted phenotypes of the VSMCs in the arterial wall for a loss of axial (E) and circumferential residual stress (F). White cells represent homeostatic VSMCs, blue cells represent progressively more synthetic VSMCs, and red cells represent progressively more contractile VSMCs. The percentages indicate the amount of residual stress present in the material. In all figures, the arterial wall runs from the luminal side on the left to the outside on the right. Percentages indicate the amount of axial or circumferential pre-stretch that was lost.

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  Fig. 8. Effects of Notch manipulations on NICD content and VSMC phenotype. Predicted NICD levels of the VSMCs in the arterial wall for changes in Notch expression (A) and Jagged expression (B). Predicted phenotypes of the VSMCs in the arterial wall for changes in Notch expression (C) and Jagged expression (D). White cells represent homeostatic VSMCs, blue cells represent progressively more synthetic VSMCs, and red cells represent progressively more contractile VSMCs. In all figures, the arterial wall runs from the luminal side on the left to the outside on the right. Percentages indicate the relative Notch or Jagged expression levels.