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

Jordy G.M. van Asten; Tommaso Ristori; David R. Nolan; Caitríona Lally; Frank P.T. Baaijens; Cecilia M. Sahlgren; Sandra Loerakker

doi:10.1016/j.jmbbm.2022.105325

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

Jordy G.M. van Asten, Tommaso Ristori, David R. Nolan, Caitríona Lally, Frank P.T. Baaijens, Cecilia M. Sahlgren, Sandra Loerakker (Corresponding author)

Onderzoeksoutput: Bijdrage aan tijdschrift › Tijdschriftartikel › Academic › peer review

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Arteries grow and remodel in response to mechanical stimuli. Hypertension, for example, results in arterial wall thickening. Cell-cell Notch signaling between vascular smooth muscle cells (VSMCs) is known to be involved in this process, but the underlying mechanisms are still unclear. Here, we investigated whether Notch mechanosensitivity to strain may regulate arterial thickening in hypertension. We developed a multiscale computational framework by coupling a finite element model of arterial mechanics, including residual stress, to an agent-based model of mechanosensitive Notch signaling, to predict VSMC phenotypes as an indicator of growth and remodeling. Our simulations revealed that the sensitivity of Notch to strain at mean blood pressure may be a key mediator of arterial thickening in hypertensive arteries. Further simulations showed that loss of residual stress can have synergistic effects with hypertension, and that changes in the expression of Notch receptors, but not Jagged ligands, may be used to control arterial growth and remodeling and to intensify or counteract hypertensive thickening. Overall, we identify Notch mechanosensitivity as a potential mediator of vascular adaptation, and we present a computational framework that can facilitate the testing of new therapeutic and regenerative strategies.

Originele taal-2	Engels
Artikelnummer	105325
Aantal pagina's	15
Tijdschrift	Journal of the Mechanical Behavior of Biomedical Materials
Volume	133
DOI's	https://doi.org/10.1016/j.jmbbm.2022.105325
Status	Gepubliceerd - sep. 2022

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Publisher Copyright:
© 2022

Financiering

This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC StG MechanoSignaling [Grant Agreement No. 802967 ] and ERC CoG ForceMorph [Grant Agreement No. 771168 ]) and from the Marie-Sklodowska-Curie Global Fellowship (grant number 846617 ). The authors wish to acknowledge Tim van Nuland for his computational assistance in performing the calibration of the circumferential residual stress. Arteries are well known to thicken in response to hypertension (Wolinsky, 1970; Vaishnav et al., 1990; Matsumoto and Hayashi, 1994; Hayashi and Sugimoto, 2007). Notch signaling regulates this process (Li et al., 2009; Qiao et al., 2012; Ragot et al., 2016), but the underlying mechanisms have remained unclear. Our simulations showed that Notch mechanosensitivity can explain arterial thickening in response to hypertension ( Fig. 3B,E,H, 4B,E,H, and 5B,E,H). Supporting this conclusion, our model also predicted that G&R activity was highest in arteries subjected to CH (Fig. 5H), followed by ISH (Fig. 3H) and IDH (Fig. 4H), which agrees with experimental observations (Manios et al., 2015; Monzo et al., 2021). These results suggest the hypothesis that Notch mechanosensitivity is involved not only in the establishment of arterial homeostasis (Loerakker et al., 2018), but also in its maintenance.This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC StG MechanoSignaling [Grant Agreement No. 802967] and ERC CoG ForceMorph [Grant Agreement No. 771168]) and from the Marie-Sklodowska-Curie Global Fellowship (grant number 846617). The authors wish to acknowledge Tim van Nuland for his computational assistance in performing the calibration of the circumferential residual stress.

Financiers	Financiernummer
European Union’s Horizon Europe research and innovation programme
International Society of Hypertension
European Research Council
Horizon 2020	846617, 771168, 802967

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10.1016/j.jmbbm.2022.105325

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Data belonging to the publication: "Computational analysis of the role of mechanosensitive Notch signaling in arterial adaptation to hypertension"
van Asten, J. G. M. (Bijdrager), Ristori, T. (Ontwerper), Nolan, D. R. (Ontwerper), Lally, C. (Ontwerper), Baaijens, F. P. T. (Ontwerper), Sahlgren, C. M. (Ontwerper) & Loerakker, S. (Ontwerper), 4TU.Centre for Research Data, 7 jul. 2022
DOI: 10.4121/20237562, https://data.4tu.nl/articles/_/20237562
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title = "Computational analysis of the role of mechanosensitive Notch signaling in arterial adaptation to hypertension",

abstract = "Arteries grow and remodel in response to mechanical stimuli. Hypertension, for example, results in arterial wall thickening. Cell-cell Notch signaling between vascular smooth muscle cells (VSMCs) is known to be involved in this process, but the underlying mechanisms are still unclear. Here, we investigated whether Notch mechanosensitivity to strain may regulate arterial thickening in hypertension. We developed a multiscale computational framework by coupling a finite element model of arterial mechanics, including residual stress, to an agent-based model of mechanosensitive Notch signaling, to predict VSMC phenotypes as an indicator of growth and remodeling. Our simulations revealed that the sensitivity of Notch to strain at mean blood pressure may be a key mediator of arterial thickening in hypertensive arteries. Further simulations showed that loss of residual stress can have synergistic effects with hypertension, and that changes in the expression of Notch receptors, but not Jagged ligands, may be used to control arterial growth and remodeling and to intensify or counteract hypertensive thickening. Overall, we identify Notch mechanosensitivity as a potential mediator of vascular adaptation, and we present a computational framework that can facilitate the testing of new therapeutic and regenerative strategies.",

keywords = "Arteries, Humans, Hypertension, Jagged-1 Protein/genetics, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle/physiology",

author = "{van Asten}, {Jordy G.M.} and Tommaso Ristori and Nolan, {David R.} and Caitr{\'i}ona Lally and Baaijens, {Frank P.T.} and Sahlgren, {Cecilia M.} and Sandra Loerakker",

note = "Funding Information: This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC StG MechanoSignaling [Grant Agreement No. 802967 ] and ERC CoG ForceMorph [Grant Agreement No. 771168 ]) and from the Marie-Sklodowska-Curie Global Fellowship (grant number 846617 ). The authors wish to acknowledge Tim van Nuland for his computational assistance in performing the calibration of the circumferential residual stress. Funding Information: Arteries are well known to thicken in response to hypertension (Wolinsky, 1970; Vaishnav et al., 1990; Matsumoto and Hayashi, 1994; Hayashi and Sugimoto, 2007). Notch signaling regulates this process (Li et al., 2009; Qiao et al., 2012; Ragot et al., 2016), but the underlying mechanisms have remained unclear. Our simulations showed that Notch mechanosensitivity can explain arterial thickening in response to hypertension ( Fig. 3B,E,H, 4B,E,H, and 5B,E,H). Supporting this conclusion, our model also predicted that G&R activity was highest in arteries subjected to CH (Fig. 5H), followed by ISH (Fig. 3H) and IDH (Fig. 4H), which agrees with experimental observations (Manios et al., 2015; Monzo et al., 2021). These results suggest the hypothesis that Notch mechanosensitivity is involved not only in the establishment of arterial homeostasis (Loerakker et al., 2018), but also in its maintenance.This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC StG MechanoSignaling [Grant Agreement No. 802967] and ERC CoG ForceMorph [Grant Agreement No. 771168]) and from the Marie-Sklodowska-Curie Global Fellowship (grant number 846617). The authors wish to acknowledge Tim van Nuland for his computational assistance in performing the calibration of the circumferential residual stress. ",

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AU - van Asten, Jordy G.M.

AU - Ristori, Tommaso

AU - Nolan, David R.

AU - Lally, Caitríona

AU - Baaijens, Frank P.T.

AU - Sahlgren, Cecilia M.

AU - Loerakker, Sandra

N1 - Funding Information: This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC StG MechanoSignaling [Grant Agreement No. 802967 ] and ERC CoG ForceMorph [Grant Agreement No. 771168 ]) and from the Marie-Sklodowska-Curie Global Fellowship (grant number 846617 ). The authors wish to acknowledge Tim van Nuland for his computational assistance in performing the calibration of the circumferential residual stress. Funding Information: Arteries are well known to thicken in response to hypertension (Wolinsky, 1970; Vaishnav et al., 1990; Matsumoto and Hayashi, 1994; Hayashi and Sugimoto, 2007). Notch signaling regulates this process (Li et al., 2009; Qiao et al., 2012; Ragot et al., 2016), but the underlying mechanisms have remained unclear. Our simulations showed that Notch mechanosensitivity can explain arterial thickening in response to hypertension ( Fig. 3B,E,H, 4B,E,H, and 5B,E,H). Supporting this conclusion, our model also predicted that G&R activity was highest in arteries subjected to CH (Fig. 5H), followed by ISH (Fig. 3H) and IDH (Fig. 4H), which agrees with experimental observations (Manios et al., 2015; Monzo et al., 2021). These results suggest the hypothesis that Notch mechanosensitivity is involved not only in the establishment of arterial homeostasis (Loerakker et al., 2018), but also in its maintenance.This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC StG MechanoSignaling [Grant Agreement No. 802967] and ERC CoG ForceMorph [Grant Agreement No. 771168]) and from the Marie-Sklodowska-Curie Global Fellowship (grant number 846617). The authors wish to acknowledge Tim van Nuland for his computational assistance in performing the calibration of the circumferential residual stress.

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N2 - Arteries grow and remodel in response to mechanical stimuli. Hypertension, for example, results in arterial wall thickening. Cell-cell Notch signaling between vascular smooth muscle cells (VSMCs) is known to be involved in this process, but the underlying mechanisms are still unclear. Here, we investigated whether Notch mechanosensitivity to strain may regulate arterial thickening in hypertension. We developed a multiscale computational framework by coupling a finite element model of arterial mechanics, including residual stress, to an agent-based model of mechanosensitive Notch signaling, to predict VSMC phenotypes as an indicator of growth and remodeling. Our simulations revealed that the sensitivity of Notch to strain at mean blood pressure may be a key mediator of arterial thickening in hypertensive arteries. Further simulations showed that loss of residual stress can have synergistic effects with hypertension, and that changes in the expression of Notch receptors, but not Jagged ligands, may be used to control arterial growth and remodeling and to intensify or counteract hypertensive thickening. Overall, we identify Notch mechanosensitivity as a potential mediator of vascular adaptation, and we present a computational framework that can facilitate the testing of new therapeutic and regenerative strategies.

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KW - Hypertension

KW - Jagged-1 Protein/genetics

KW - Muscle, Smooth, Vascular

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

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