Abstract
Hypertension is both a cause and a consequence of central artery stiffening, which in turn is an initiator and indicator of myriad disease conditions and thus all-cause mortality. Such ...stiffening results from a remodeling of the arterial wall that is driven by mechanical stimuli and mediated by inflammatory signals, which together lead to differential gene expression and concomitant changes in extracellular matrix composition and organization. This review focuses on biomechanical mechanisms by which central arteries remodel in hypertension within the context of homeostasis—what promotes it, what prevents it. It is suggested that the vasoactive capacity of the wall and inflammatory burden strongly influence the ability of homeostatic mechanisms to adapt the arterial wall to high blood pressure or not. Maladaptation, often reflected by inflammation-driven adventitial fibrosis, not just excessive intimal–medial thickening, significantly diminishes central artery function and disturbs hemodynamics, ultimately compromising end organ perfusion and thus driving the associated morbidity and mortality. It is thus suggested that there is a need for increased attention to controlling both smooth muscle phenotype and inflammation in hypertensive remodeling of central arteries, with future studies of the often adaptive response of medium-sized muscular arteries promising to provide additional guidance.
Graphical Abstract
Graphical Abstract
Arterial stiffness, a leading marker of risk in hypertension, can be measured at material or structural levels, with the latter combining effects of the geometry and composition of the wall, ...including intramural organization. Numerous studies have shown that structural stiffness predicts outcomes in models that adjust for conventional risk factors. Elastic arteries, nearer to the heart, are most sensitive to effects of blood pressure and age, major determinants of stiffness. Stiffness is usually considered as an index of vascular aging, wherein individuals excessively affected by risk factor exposure represent early vascular aging, whereas those resistant to risk factors represent supernormal vascular aging. Stiffness affects the function of the brain and kidneys by increasing pulsatile loads within their microvascular beds, and the heart by increasing left ventricular systolic load; excessive pressure pulsatility also decreases diastolic pressure, necessary for coronary perfusion. Stiffness promotes inward remodeling of small arteries, which increases resistance, blood pressure, and in turn, central artery stiffness, thus creating an insidious feedback loop. Chronic antihypertensive treatments can reduce stiffness beyond passive reductions due to decreased blood pressure. Preventive drugs, such as lipid-lowering drugs and antidiabetic drugs, have additional effects on stiffness, independent of pressure. Newer anti-inflammatory drugs also have blood pressure independent effects. Reduction of stiffness is expected to confer benefit beyond the lowering of pressure, although this hypothesis is not yet proven. We summarize different steps for making arterial stiffness measurement a keystone in hypertension management and cardiovascular prevention as a whole.
Cells of the vascular wall are exquisitely sensitive to changes in their mechanical environment. In healthy vessels, mechanical forces regulate signaling and gene expression to direct the remodeling ...needed for the vessel wall to maintain optimal function. Major diseases of arteries involve maladaptive remodeling with compromised or lost homeostatic mechanisms. Whereas homeostasis invokes negative feedback loops at multiple scales to mediate mechanobiological stability, disease progression often occurs via positive feedback that generates mechanobiological instabilities. In this review, we focus on the cell biology, wall mechanics, and regulatory pathways associated with arterial health and how changes in these processes lead to disease. We discuss how positive feedback loops arise via biomechanical and biochemical means. We conclude that inflammation plays a central role in overriding homeostatic pathways and suggest future directions for addressing therapeutic needs.
Modeling the transport, activation, and adhesion of platelets is crucial in predicting thrombus formation and growth following a thrombotic event in normal or pathological conditions. We propose a ...shear-dependent platelet adhesive model based on the Morse potential that is calibrated by existing in vivo and in vitro experimental data and can be used over a wide range of flow shear rates (Formula: see text). We introduce an Eulerian-Lagrangian model where hemodynamics is solved on a fixed Eulerian grid, while platelets are tracked using a Lagrangian framework. A force coupling method is introduced for bidirectional coupling of platelet motion with blood flow. Further, we couple the calibrated platelet aggregation model with a tissue-factor/contact pathway coagulation cascade, representing the relevant biology of thrombin generation and the subsequent fibrin deposition. The range of shear rates covered by the proposed model encompass venous and arterial thrombosis, ranging from low-shear-rate conditions in abdominal aortic aneurysms and thoracic aortic dissections to thrombosis in stenotic arteries following plaque rupture, where local shear rates are extremely high.
We employ physics-informed neural networks (PINNs) to infer properties of biological materials using synthetic data. In particular, we successfully apply PINNs to extract the permeability and ...viscoelastic modulus from thrombus deformation data, which can be described by the fourth-order Cahn–Hilliard and Navier–Stokes Equations. In PINNs, the partial differential equations are encoded into a loss function, where partial derivatives can be obtained through automatic differentiation (AD). To tackle the challenge of calculating the fourth-order derivative in the Cahn–Hilliard equation with AD, we introduce an auxiliary network along with the main neural network to approximate the second-derivative of the energy potential term. Our model can simultaneously predict unknown material parameters and velocity, pressure, and deformation gradient fields by merely training with partial information among all data, i.e., phase field and pressure measurements, while remaining highly flexible in sampling within the spatio-temporal domain for data acquisition. We validate our model by numerical solutions from the spectral/hp element method (SEM) and demonstrate its robustness by training it with noisy measurements. Our results show that PINNs can infer the material properties from noisy synthetic data ►and thus they have great potential for inferring these properties from experimental multi-modality and multi-fidelity data.
Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties ...of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.
Arterial growth and remodeling at the tissue level is driven by mechanobiological processes at cellular and sub-cellular levels. Although it is widely accepted that cells seek to promote tissue ...homeostasis in response to biochemical and biomechanical cues-such as increased wall stress in hypertension-the ways by which these cues translate into tissue maintenance, adaptation, or maladaptation are far from understood. In this paper, we present a logic-based computational model for cell signaling within the arterial wall, aiming to predict changes in extracellular matrix turnover and cell phenotype in response to pressure-induced wall stress, flow-induced wall shear stress, and exogenous sources of angiotensin II, with particular interest in mouse models of hypertension. We simulate a number of experiments from the literature at both the cell and tissue level, involving single or combined inputs, and achieve high qualitative agreement in most cases. Additionally, we demonstrate the utility of this modeling approach for simulating alterations (in this case knockdowns) of individual nodes within the signaling network. Continued modeling of cellular signaling will enable improved mechanistic understanding of arterial growth and remodeling in health and disease, and will be crucial when considering potential pharmacological interventions.
Mechanical interactions between flowing and coagulated blood (thrombus) are crucial in dictating the deformation and remodeling of a thrombus after its formation in hemostasis. We propose a ...fully-Eulerian, three-dimensional, phase-field model of thrombus that is calibrated with existing in vitro experimental data. This phase-field model considers spatial variations in permeability and material properties within a single unified mathematical framework derived from an energy perspective, thereby allowing us to study effects of thrombus microstructure and properties on its deformation and possible release of emboli under different hemodynamic conditions. Moreover, we combine this proposed thrombus model with a particle-based model which simulates the initiation of the thrombus. The volume fraction of a thrombus obtained from the particle simulation is mapped to an input variable in the proposed phase-field thrombus model. The present work is thus the first computational study to integrate the initiation of a thrombus through platelet aggregation with its subsequent viscoelastic responses to various shear flows. This framework can be informed by clinical data and potentially be used to predict the risk of diverse thromboembolic events under physiological and pathological conditions.
One of the most remarkable differences between classical engineering materials and living matter is the ability of the latter to grow and remodel in response to diverse stimuli. The mechanical ...behaviour of living matter is governed not only by an elastic or viscoelastic response to loading on short time scales up to several minutes, but also by often crucial growth and remodelling responses on time scales from hours to months. Phenomena of growth and remodelling play important roles, for example during morphogenesis in early life as well as in homeostasis and pathogenesis in adult tissues, which often adapt to changes in their chemo-mechanical environment as a result of ageing, diseases, injury or surgical intervention. Mechano-regulated growth and remodelling are observed in various soft tissues, ranging from tendons and arteries to the eye and brain, but also in bone, lower organisms and plants. Understanding and predicting growth and remodelling of living systems is one of the most important challenges in biomechanics and mechanobiology. This article reviews the current state of growth and remodelling as it applies primarily to soft tissues, and provides a perspective on critical challenges and future directions.
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