Investigating metalloproteinases MMP-2 and MMP-9 mechanosensitivity to feedback loops involved in the regulation of in vitro angiogenesis by endogenous mechanical stresses.

Angiogenesis is a complex morphogenetic process regulated by growth factors, but also by the force balance between endothelial cells (EC) traction stresses and extracellular matrix (ECM) viscoelastic resistance. Studies conducted with in vitro angiogenesis assays demonstrated that decreasing ECM stiffness triggers an angiogenic switch that promotes organization of EC into tubular cords or pseudo-capillaries. Thus, mechano-sensitivity of EC with regard to proteases secretion, and notably matrix metalloproteinases (MMPs), should likely play a pivotal role in this switching mechanism.

Elucidating atherosclerotic vulnerable plaque rupture by modeling cross substitution of ApoE-/- mouse and human plaque components stiffnesses.

The structure of mouse atherosclerotic lesions may differ from that of humans, and mouse atherosclerotic plaques do not rupture except in some specific locations such as the brachiocephalic artery. Recently, our group was the first to observe that the amplitudes of in vivo stresses in ApoE-/- mouse aortic atherosclerotic lesions were much lower and differed from those found in a previous work performed on human lesions. In this previous preliminary work, we hypothesized that the plaque mechanical properties (MP) may in turn be responsible for such species differences.

Robustness analysis and behavior discrimination in enzymatic reaction networks.

Characterizing the behavior and robustness of enzymatic networks with numerous variables and unknown parameter values is a major challenge in biology, especially when some enzymes have counter-intuitive properties or switch-like behavior between activation and inhibition. In this paper, we propose new methodological and tool-supported contributions, based on the intuitive formalism of temporal logic, to express in a rigorous manner arbitrarily complex dynamical properties. Our multi-step analysis allows efficient sampling of the parameter space in order to define feasible regions in which the model exhibits imposed or experimentally observed behaviors.

Is arterial wall-strain stiffening an additional process responsible for atherosclerosis in coronary bifurcations?: an in vivo study based on dynamic CT and MRI.

Coronary bifurcations represent specific regions of the arterial tree that are susceptible to atherosclerotic lesions. While the effects of vessel compliance, curvature, pulsatile blood flow, and cardiac motion on coronary endothelial shear stress have been widely explored, the effects of myocardial contraction on arterial wall stress/strain (WS/S) and vessel stiffness distributions remain unclear. Local increase of vessel stiffness resulting from wall-strain stiffening phenomenon (a local process due to the nonlinear mechanical properties of the arterial wall) may be critical in the development of atherosclerotic lesions.

Assessing low levels of mechanical stress in aortic atherosclerotic lesions from apolipoprotein E-/- mice--brief report.

Objective: Despite the fact that mechanical stresses are well recognized as key determinants for atherosclerotic plaque rupture, very little is known about stress amplitude and distribution in atherosclerotic lesions, even in the standard apolipoprotein E (apoE)-/- mouse model of atherosclerosis. Our objectives were to combine immunohistology, atomic force microscopy measurements, and finite element computational analysis for the accurate quantification of stress amplitude and distribution in apoE-/- mouse aortic atherosclerotic lesions.

Methods And Results: Residual stresses and strains were released by radially cutting aortic arch segments from 7- to 30-week-old pathological apoE-/- (n=25) and healthy control mice (n=20).

Mapping elasticity moduli of atherosclerotic plaque in situ via atomic force microscopy.

Several studies have suggested that evolving mechanical stresses and strains drive atherosclerotic plaque development and vulnerability. Especially, stress distribution in the plaque fibrous capsule is an important determinant for the risk of vulnerable plaque rupture. Knowledge of the stiffness of atherosclerotic plaque components is therefore of critical importance.

On the potential of a new IVUS elasticity modulus imaging approach for detecting vulnerable atherosclerotic coronary plaques: in vitro vessel phantom study.

Peak cap stress amplitude is recognized as a good indicator of vulnerable plaque (VP) rupture. However, such stress evaluation strongly relies on a precise, but still lacking, knowledge of the mechanical properties exhibited by the plaque components. As a first response to this limitation, our group recently developed, in a previous theoretical study, an original approach, called iMOD (imaging modulography), which reconstructs elasticity maps (or modulograms) of atheroma plaques from the estimation of strain fields.

Functionalization of matrices by cyclically stretched osteoblasts through matrix targeting of VEGF.

Vascular endothelial growth factor A (VEGF) plays a central role in load-induced bone gain. We previously showed that increasing cyclic stretch frequency from 0.05 to 5 Hz induce parallel increased in entrapment of VEGF (mVEGF) into osteoblast secreted extracellular matrix.

Unraveling changes in myocardial contractility during human fetal growth: a finite element analysis based on in vivo ultrasound measurements.

Knowledge of normal fetal heart (FH) performance and development is crucial for evaluating and understanding how various congenital heart lesions may modify heart contractility during the gestational period. However, since biomechanical models of FH are still lacking, structural approaches proposed to describe the mechanical behavior of the adult human heart cannot be used to model the evolution of the FH. In this paper, a finite element model of the healthy FH wall is developed to quantify its mechanical properties during the gestational period.

An integrated formulation of anisotropic force-calcium relations driving spatio-temporal contractions of cardiac myocytes.

Isolated cardiac myocytes exhibit spontaneous patterns of rhythmic contraction, driven by intracellular calcium waves. In order to study the coupling between spatio-temporal calcium dynamics and cell contraction in large deformation regimes, a new strain-energy function, describing the influence of sarcomere length on the calcium-dependent generation of active intracellular stresses, is proposed. This strain-energy function includes anisotropic passive and active contributions that were first validated separately from experimental stress-strain curves and stress-sarcomere length curves, respectively.

Nonlinear elastic properties of polyacrylamide gels: implications for quantification of cellular forces.

Because of their tunable mechanical properties, polyacrylamide gels (PAG) are frequently used for studying cell adhesion and migratory responses to extracellular substrate stiffness. Since these responses are known to heavily depend on the tensional balance between cell contractility and substrate mechanical resistance, a precise knowledge of PAG's mechanical properties becomes quite crucial. Using the micropipette aspiration technique, we first exhibited the nonlinear elastic behavior of PAG and then successfully modeled it by an original strain-energy function.

Vulnerable atherosclerotic plaque elasticity reconstruction based on a segmentation-driven optimization procedure using strain measurements: theoretical framework.

It is now recognized that prediction of the vulnerable coronary plaque rupture requires not only an accurate quantification of fibrous cap thickness and necrotic core morphology but also a precise knowledge of the mechanical properties of plaque components. Indeed, such knowledge would allow a precise evaluation of the peak cap-stress amplitude, which is known to be a good biomechanical predictor of plaque rupture. Several studies have been performed to reconstruct a Young's modulus map from strain elastograms.

Quantification of cardiomyocyte contraction based on image correlation analysis.

Quantification of cardiomyocyte contraction is usually obtained by measuring globally cell shortening from the displacement of cell extremities. We developed a correlation-based optical flow method, which correlates the whole-cell temporal pattern with a precise quantification of the intracellular strain wave at the sarcomeres level. A two-dimensional image correlation analysis of cardiomyocytes phase-contrast images was developed to extract local cell deformations from videomicroscopy time-lapse sequences.

Theoretical analysis of the adaptive contractile behaviour of a single cardiomyocyte cultured on elastic substrates with varying stiffness.

In vivo, cardiomyocytes interact with surrounding extracellular matrix while performing periodically a contractile behaviour, which is the main determinant of heart performance. As extracellular substrates with easily tunable stiffness properties, polyacrylamide gels (PAGs) provide valuable flexible media for studying in vitro the dynamical behaviour of cardiomyocytes responding to stiffness variations of their surrounding environment. We propose in this paper an original mechano-chemical model of the cardiac cell contraction that sheds light on the adaptive response of cardiomyocytes evidenced recently in the experiments of Qin et al.

Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture.

Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Core(area)) and the arterial remodeling index (Remod(index)), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Core(area) thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Core(area) and Remod(index), it remains unclear how these interact and affect peak cap stress (Cap(stress)), a known predictor of rupture.

A computational model of cell migration coupling the growth of focal adhesions with oscillatory cell protrusions.

Cell migration is a highly integrated process where actin turnover, actomyosin contractility, and adhesion dynamics are all closely linked. In this paper, we propose a computational model investigating the coupling of these fundamental processes within the context of spontaneous (i.e.

The motility of normal and cancer cells in response to the combined influence of the substrate rigidity and anisotropic microstructure.

Cell adhesion and migration are strongly influenced by extracellular matrix (ECM) architecture and rigidity, but little is known about the concomitant influence of such environmental signals to cell responses, especially when considering cells of similar origin and morphology, but exhibiting a normal or cancerous phenotype. Using micropatterned polydimethylsiloxane substrates (PDMS) with tunable stiffness (500 kPa, 750 kPa, 2000 kPa) and topography (lines, pillars or unpatterned), we systematically analyse the differential response of normal (3T3) and cancer (SaI/N) fibroblastic cells. Our results demonstrate that both cells exhibit differential morphology and motility responses to changes in substrate rigidity and microtopography.

Influences of adhesion area and biological sample size on the estimation of Young's modulus and Poisson's ratio assessed by micropipette aspiration technique.

The micropipette aspiration experiment remains a widely used micromanipulation technique for quantifying the mechanical properties of biological samples. Our study extends previous results by investigating the influence of sample size and adhesion area on the mechanical response of compressible thin biological samples. We thus defined a nonlinear relationship between aspirated length, Young's modulus, Poisson's ratio and sample thickness which allowed us to develop an original experimental protocol for simultaneous quantification of the Poisson's ratio and Young's modulus of adherent samples.

Morphological and biomechanical aspects of vulnerable coronary plaque.

Vulnerable plaque morphology has been described by gross pathology and intravascular ultrasound, but morphological criteria cannot fully explain vulnerability, which involves four distinct factors: 1) inflammatory and biological processes; 2) geometry; 3) composition; and 4) hemodynamic stress. These last three aspects underlie the biomechanical study of vulnerable plaque. By virtue of the nature of their evolution, atherosclerotic plaques tend to be excentric, and this is a crucial morphological feature, causing circumferential stress to peak in very specific juxta-luminal locations, where it can exceed the rupture threshold of collagen, the basic constituent of arterial architecture.

Estimation of cell Young's modulus of adherent cells probed by optical and magnetic tweezers: influence of cell thickness and bead immersion.

A precise characterization of cell elastic properties is crucial for understanding the mechanisms by which cells sense mechanical stimuli and how these factors alter cellular functions. Optical and magnetic tweezers are micromanipulation techniques which are widely used for quantifying the stiffness of adherent cells from their response to an external force applied on a bead partially embedded within the cell cortex. However, the relationships between imposed external force and resulting bead translation or rotation obtained from these experimental techniques only characterize the apparent cell stiffness.

Influence of residual stress/strain on the biomechanical stability of vulnerable coronary plaques: potential impact for evaluating the risk of plaque rupture.

In a vulnerable plaque (VP), rupture often occurs at a site of high stress within the cap. It is also known that vessels do not become free of stress when all external loads are removed. Previous studies have shown that such residual stress/strain (RS/S) tends to make the stress distribution more uniform throughout the media of a normal artery.

The rigidity in fibrin gels as a contributing factor to the dynamics of in vitro vascular cord formation.

While the formation of vascular cords in in vitro angiogenesis assay is commonly used to test the angiogenic properties of many molecular or cellular components, an extensive characterisation of the dynamics of this process is still lacking. Up to now, quantitative studies only focused on the resulting capillary structures characterised through static morphometric approaches. We therefore propose in this paper a rather extensive characterisation aiming to identify different stages in the dynamics of this process, through the investigation of the influence of the rigidity of the fibrin extracellular matrix on the growth of the vascular cords.

An extended relationship for the characterization of Young's modulus and Poisson's ratio of tunable polyacrylamide gels.

Substrates with tunable mechanical properties are crucial for the study of cellular processes, and polyacrylamide gels (PAGs) are frequently used in this context. Several experimental techniques have been proposed to obtain the mechanical properties of PAGs. However, the range of the considered Poisson's ratio values remains quite large and no attempt has been made to propose an analytical relationship allowing the estimation of PAG Young's modulus when both bis-acrylamide and acrylamide concentrations are known.

QxDB: a generic database to support mathematical modelling in biology.

QxDB (quantitative x-modelling database) is a web-based generic database package designed especially to house quantitative and structural information. Its development was motivated by the need for centralized access to such results for development of mathematical models, but its usefulness extends to the general research community of both modellers and experimentalists. Written in PHP (Hyper Preprocessor) and MYSQL, the database is easily adapted to new fields of research and ported to Apache-based web servers.