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Mechanochemical Modeling of Smooth Muscle Activation
KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Smooth muscle has an important role in several physiological processes, where it regulates the wall tension and the size of hollow organs. In blood vessels, the contraction and relaxation of smooth muscle contribute to the mechanical stability of the vessel wall and determines the diameter. To better understand how the active tone of smooth muscle influences the passive layers of the artery wall and how dysfunctions of the smooth muscle are related to pathologies such as hypertension and vasospasm, a coupled chemomechanical model based on structural studies and contractile behavior was proposed in this thesis. Smooth muscle contraction arises when cross-bridges between the myosin and actin filament cycle, causing sliding of the filaments. The contraction is triggered when myosin is phosphorylated by an influx of intracellular calcium ions, which can be initiated through different excitation-contraction pathways.

The proposed model coupled a chemical model, where intracellular calcium ion concentration was related to myosin phosphorylation and the fraction of load-bearing cross-bridges, with a mechanical model which was based on the three-element Hill model. The mechanical model, which described a sarcomeric equivalent contractile unit based on structural observations had been developed and modified in different steps to capture the characteristics of smooth muscle behavior, such as isometric contraction, isotonic shortening velocities and length-tension relationships. The chemical material parameters were fitted to calcium-phosphorylation data found in the literature and the mechanical model was fitted against experiments on swine common carotid media performed at Karolinska Instititet, Stockholm. The final coupled model was implemented into a three-dimensional finite element code to simulate the active tone in a two layered artery exposed to realistic pressure pulses. Simulation results indicated that changes in intracellular calcium amplitudes did not have significant effects while changes in the mean value of the intracellular calcium and in the medial wall thickness had a more significant effect on the mechanical response of the arterial wall.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. , 34 p.
Series
Trita-HFL. Report / Royal Institute of Technology, Solid mechanics, ISSN 1654-1472 ; 0517
Keyword [en]
Biomechanics, Muscle contraction, Smooth muscle, Contractile unit, Filament overlap, Intracellular calcium, Carotid artery, Mathematical model
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-66780OAI: oai:DiVA.org:kth-66780DiVA: diva2:484641
Public defence
2012-02-10, Sal F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20120127

Available from: 2012-01-27 Created: 2012-01-27 Last updated: 2013-01-14Bibliographically approved
List of papers
1. A calcium-driven mechanochemical model for prediction of force generation in smooth muscle
Open this publication in new window or tab >>A calcium-driven mechanochemical model for prediction of force generation in smooth muscle
2010 (English)In: Biomechanics and Modeling in Mechanobiology, ISSN 1617-7959, E-ISSN 1617-7940, Vol. 9, no 6, 749-762 p.Article in journal (Refereed) Published
Abstract [en]

A new model for the mechanochemical response of smooth muscle is presented. The focus is on the response of the actin-myosin complex and on the related generation of force (or stress). The chemical (kinetic) model describes the cross-bridge interactions with the thin filament in which the calcium-dependent myosin phosphorylation is the only regulatory mechanism. The new mechanical model is based on Hill's three-component model and it includes one internal state variable that describes the contraction/relaxation of the contractile units. It is characterized by a strain-energy function and an evolution law incorporating only a few material parameters with clear physical meaning. The proposed model satisfies the second law of thermodynamics. The results of the combined coupled model are broadly consistent with isometric and isotonic experiments on smooth muscle tissue. The simulations suggest that the matrix in which the actin-myosin complex is embedded does have a viscous property. It is straightforward for implementation into a finite element program in order to solve more complex boundary-value problems such as the control of short-term changes in lumen diameter of arteries due to mechanochemical signals.

Keyword
Biomechanics, Calcium, Kinetic model, Mechanical model, Mechanochemical, Smooth muscle contraction
National Category
Applied Mechanics
Identifiers
urn:nbn:se:kth:diva-25400 (URN)10.1007/s10237-010-0211-0 (DOI)000284518200008 ()2-s2.0-78049334279 (Scopus ID)
Funder
Swedish Research Council, 2005-6167
Note
QC 20101020Available from: 2010-10-20 Created: 2010-10-20 Last updated: 2017-12-12Bibliographically approved
2. Modeling the dispersion effects of contractile fibers in smooth muscles
Open this publication in new window or tab >>Modeling the dispersion effects of contractile fibers in smooth muscles
2010 (English)In: Journal of the mechanics and physics of solids, ISSN 0022-5096, E-ISSN 1873-4782, Vol. 58, no 12, 2065-2082 p.Article in journal (Refereed) Published
Abstract [en]

Micro-structurally based models for smooth muscle contraction are crucial for a better understanding of pathological conditions such as atherosclerosis, incontinence and asthma. It is meaningful that models consider the underlying mechanical structure and the biochemical activation. Hence, a simple mechanochemical model is proposed that includes the dispersion of the orientation of smooth muscle myofilaments and that is capable to capture available experimental data on smooth muscle contraction. This allows a refined study of the effects of myofilament dispersion on the smooth muscle contraction. A classical biochemical model is used to describe the cross-bridge interactions with the thin filament in smooth muscles in which calcium-dependent myosin phosphorylation is the only regulatory mechanism. A novel mechanical model considers the dispersion of the contractile fiber orientations in smooth muscle cells by means of a strain-energy function in terms of one dispersion parameter. All model parameters have a biophysical meaning and may be estimated through comparisons with experimental data. The contraction of the middle layer of a carotid artery is studied numerically. Using a tube the relationships between the internal pressure and the stretches are investigated as functions of the dispersion parameter, which implies a strong influence of the orientation of smooth muscle myofilaments on the contraction response. It is straightforward to implement this model in a finite element code to better analyze more complex boundary-value problems.

Keyword
Artery, Biomechanics, Calcium, Dispersion, Smooth muscle contraction
National Category
Applied Mechanics
Identifiers
urn:nbn:se:kth:diva-25401 (URN)10.1016/j.jmps.2010.09.003 (DOI)000284568900005 ()2-s2.0-78049337618 (Scopus ID)
Note
QC 20101020Available from: 2010-10-20 Created: 2010-10-20 Last updated: 2017-12-12Bibliographically approved
3. Experiments and mechanochemical modeling of smooth muscle contraction: Significance of filament overlap.
Open this publication in new window or tab >>Experiments and mechanochemical modeling of smooth muscle contraction: Significance of filament overlap.
2012 (English)In: Journal of Theoretical Biology, ISSN 0022-5193, E-ISSN 1095-8541, Vol. 297, 176-186 p.Article in journal (Refereed) Published
Abstract [en]

The main function of smooth muscle is to maintain/regulate the size of different hollow organs through contraction and relaxation. The magnitude of the active force during contraction is dependent on the number of attached cross-bridges, which can be linked to the overlap between the thin and thick filaments. The relevance of filament overlap and the active cross-bridges in smooth muscle is investigated through a mechanical model founded on Hill's three-element model. The mechanical model describes a sarcomere-equivalent contractile unit supported by structural observations with a distinct filament overlap and a realistic framework for the filament sliding behavior based on force-velocity experiments. The mechanical model is coupled to the four-state latch-model by Hai and Murphy to capture the electromechanical activation from intracellular calcium concentration to load-bearing cross-bridges. The model is fitted to isometric experiments performed on the pig carotid media and on isotonic quick-release experiments found in the literature. The proposed coupled mechanochemical model with the description of the filament overlap, which has a significant influence on the results, is able to predict isometric experimental data performed at different muscle lengths. The relevance of the filament overlap and the load-bearing cross-bridges is investigated through the model by simulating additional scenarios that has been documented in the literature.

Keyword
Smooth muscle, Muscle contraction, Contractile unit, Filament overlap, Modeling
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-66749 (URN)10.1016/j.jtbi.2011.11.012 (DOI)000300652000017 ()22108241 (PubMedID)2-s2.0-84856736341 (Scopus ID)
Note
QC 20120127Available from: 2012-01-27 Created: 2012-01-27 Last updated: 2017-12-08Bibliographically approved
4. Investigating the Role of Smooth Muscle in Carotid Arteries: A Finite Element Analysis
Open this publication in new window or tab >>Investigating the Role of Smooth Muscle in Carotid Arteries: A Finite Element Analysis
(English)Article in journal (Other academic) Submitted
Abstract [en]

Vascular smooth muscle is a slow muscle, which reach isometric active steady-state force within minutes and it is not well known how this influence the active response in arteries that are loaded to cardiac pressure cycles that act within seconds. The role of active smooth muscle in larger arteries was investigated by studying how changes in intracellular calcium and medial wall thickness affect the deformation and transmural circumferential stress in arteries when loaded with cardiac pressure pulses. A three-dimensional finite element model of a two-layer carotid arterial ring was constructed using an implemented mechanochemical model of the active smooth muscle, which couples intracellular calcium to mechanical contraction together with a hyperelastic anisotropic model representing the elastin and collagen in the arterial ring. The material parameters was taken from previous work fitted to swine carotid artery. Residual stresses and strain in arterial ring were considered by closing an initial opening angle in the arterial ring. The simulation results of the arterial ring exposed to realistic pressure pulses and varying intracellular calcium waves with same period as the pressure pulses, showed that changes in intracellular calcium amplitudes did not have significant impact on the radial deformation and the transmural stress of the arterial ring. Increase in the mean value of the intracellular calcium waves as well as in the medial wall thickness showed to have a more significant effect on the behavior of the arterial wall.

National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-66778 (URN)
Note
QS 2012. QS 20120328Available from: 2012-01-27 Created: 2012-01-27 Last updated: 2012-03-28Bibliographically approved

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