Time course of flow-induced adaptation of carotid artery biomechanical properties, structure and zero-stress state in the arteriovenous shunt

Numerous studies have provided evidence of diameter adaptation secondary to flow-overload, but with ambiguous findings vis à vis other morphological parameters and information on the biomechanical aspects of arterial adaptation is rather incomplete. We examined the time course of large-artery biomechanical adaptation elicited by long-term flow-overload in a porcine shunt model between the carotid artery and ipsilateral jugular vein. Post-shunting, the proximal artery flow was doubled and retained so until euthanasia (up to three months post-operatively), without pressure change. This hemodynamic stimulus induced lumen diameter enlargement, accommodated by elastin fragmentation and connective tissue accumulation, as witnessed by optical and confocal microscopy. Heterogeneous mass growth of the adventitia was observed at the expense of the media, associated with declining residual strains and opening angle at three months. The in vitro elastic properties of shunted arteries determined by inflation/extension testing were also modified, with the thickness-pressure curves shifted to larger thicknesses and the diameter-pressure curves shifted to larger diameters at physiologic pressures, resulting in normalization of intramural and shear stresses within fifteen and thirty days, respectively. We infer that the biomechanical adaptation in moderate flow-overload leads to normalization of intimal shear, without, however, restoring compliance and distensibility at mean in vivo pressure to control levels.     

Biomechanical, morphological and zero-stress state characterization of jugular vein remodeling in arteriovenous fistulas for hemodialysis

While the role of hemodynamic variables on the development of intimal hyperplasia in arteriovenous fistulas for hemodialysis has been examined, less is known about the intramural biomechanical factors. In this study, arteriovenous fistulas were created by implantation of e-PTFE grafts between carotid artery and jugular vein in healthy pigs. In vivo recordings exhibited a three-fold pressure and flow elevation in grafted veins after fistula creation, remaining so until sacrifice. The chief morphological observation in grafted vessels was wall thickening at two weeks, serving to restore intramural stresses to homeostatic levels, and a less marked internal diameter enlargement, gradually normalizing intimal shear after four weeks. The residual strains and opening angle, specifying the zero-stress configuration, increased with differences reaching significance at twelve weeks. Association with histomorphological findings on intima, media and adventitia growth disclosed a correlation between intimal hyperplasia and opening angle increase. Elastin and cellular contents diminished opposite to collagen content, most differences occurring within the first four weeks after grafting. Inflation/extension testing showed that post-fistula the vein wall became progressively thicker and stiffer, lacking restoration of compliance to baseline levels. The present data may further our understanding of the dynamics of venous biomechanical remodeling under pressure and flow-overload conditions.     

The determination of the collagen and elastin amount in the human varicose vein by the computer morphometric method

The results of the works dealing with alterations of the connective tissue in varicose vein wall are not ambiguous, so the exact cause of the vein dilatation has still not been established. We were determining the collagen and elastin amounts in human varicose vein wall in comparison with non-dilated long saphenous vein by the light microscopy and computer morphometric method. We have found the lesser amount of collagen in varicose veins than in non-dilated veins, the amounts of the elastin in both the varicose and non-varicose veins were without the statistical significance.     

Role of mechanosignaling on pathology of varicose vein

Varicose veins are the most common vascular disease in humans. Veins have valves that help the blood return gradually to the heart without leaking blood. When these valves become weak, blood and fluid collect and pool by pressing against the walls of the veins, causing varicose veins. In the cardiovascular system, mechanical forces are important determinants of vascular homeostasis and pathological processes. Blood vessels are constantly exposed to a variety of hemodynamic forces, including shear stress and environmental strains caused by the blood flow. In varicose veins within the leg, venous blood pressure rises in the vein of the lower extremities due to prolonged standing, creating a peripheral tension in the vessel wall thereby causing mechanical stimulation of endothelial cells and vascular smooth muscle. Studies have shown that long-term increased exposure to vascular wall tension is associated with the overexpression of HIF-1α and HIF-2α and increased levels of MMP-2 and MMP-9, thereby reducing venous contraction and progressive venous dilatation, which is involved in the development of varicose veins. Following the expression of metalloproteinase, the expression of type 1 collagen increases, and the amount of type 3 collagen decreases. Therefore, collagen imbalance will cause the varicose veins to not stretch. Loss of structural proteins (type 3 collagen and elastin) in the vessel wall causes the loss of the biophysical properties of the varicose vein wall. This review article tries to elaborate on the effect of mechanical forces and sensors of these forces on the vascular wall in creating the mechanism of mechanosignaling, as well as the role of the onset of molecular signaling cascades in the pathology of varicose veins.     

Biomechanical and histological characteristics of passive esophagus: Experimental investigation and comparative constitutive modeling

Information on the passive biomechanical properties of two-layered esophagus is still limited, although this would enhance our understanding of its physiology/pathophysiology and help to address problems in surgery, medical-device applications, and for the optimal design of prostheses. In this study, rabbit esophagi were excised and dissected into mucosa–submucosa and muscle layers that were submitted to histological quantification of elastin and collagen content and orientation, as well as to inflation-extension testing and geometrical analysis, i.e. delineation of the zero-stress state serving as a reference configuration for biomechanical analysis. The pressure–radius data of both layers displayed a monotonically rising slope with inflating pressure, unlike the sigma shape characterizing elastin-rich tissues, for which biphasic constitutive models were initially postulated. Three phenomenological expressions of strain-energy function (SEF), commonly appearing in soft-tissue biomechanics literature, were used in an attempt to model the pseudoelastic response of esophageal tissue, namely the exponential Fung-type SEF, and the combined neo-Hookean (isotropic) or quadratic (anisotropic) and exponential Fung-type SEF. Accurate fits were attained for the pressure–radius–force data, spanning a wide range of longitudinal stretch ratios, when using the exponential form; the biphasic SEFs failed to generate improved fits, being also over-parameterized. According to the calculated material parameters, mucosa–submucosa was stiffer than muscle in both directions, justified by our histological observation of increased collagen content in that layer, and tissue was stiffer longitudinally, substantiated by the increased elastin and collagen contents and their preferential alignment towards that direction. Our results demonstrate that the passive response of esophagus is best modeled with an exponential Fung-type SEF.     

In vivo estimation of the contribution of elastin and collagen to the mechanical properties in the human abdominal aorta: effect of age and sex

The mechanical properties of the aorta affect cardiac function and are related to cardiovascular morbidity/mortality. This study was designed to evaluate the isotropic (mainly elastin, elastin(iso)) and anisotropic (mainly collagen, collagen(ani)) material parameters within the human aorta in vivo. Thirty healthy men and women in three different age categories (23-30, 41-54, and 67-72 yr) were included. A novel mechanical model was used to identify the mechanical properties and the strain field with aid of simultaneously recorded pressure and radius in the abdominal aorta. The magnitudes of the material parameters relating to both the stiffness of elastin(iso) and collagen(ani) were in agreement with earlier in vitro studies. The load-bearing fraction attributed to collagen(ani) oscillated from 10 to 30% between diastolic and systolic pressures during the cardiac cycle. With age, stiffness of elastin(iso) increased in men, despite the decrease in elastin content that has been found due to elastolysis. Furthermore, an increase in stiffness of collagen(ani) at high physiological pressure was found. This might be due to increased glycation, as well as changed isoforms of collagen in the aortic wall with age. A marked sex difference was observed, with a much less age-related effect, both on elastin(iso) and collagen(ani) stiffness in women. Possible factors of importance could be the effect of sex hormones, as well as differing collagen isoforms, between the sexes.     

Matrix Metalloproteinase 9 (MMP-9) Regulates Vein Wall Biomechanics in Murine Thrombus Resolution

Objective

Deep venous thrombosis is a common vascular problem with long-term complications including post-thrombotic syndrome. Post-thrombotic syndrome consists of leg pain, swelling and ulceration that is related to incomplete or maladaptive resolution of the venous thrombus as well as loss of compliance of the vein wall. We examine the role of metalloproteinase-9 (MMP-9), a gene important in extracellular remodeling in other vascular diseases, in mediating thrombus resolution and biomechanical changes of the vein wall.

Methods and Results

The effects of targeted deletion of MMP-9 were studied in an in vivo murine model of thrombus resolution using the FVB strain of mice. MMP-9 expression and activity significantly increased on day 3 after DVT. The lack of MMP-9 impaired thrombus resolution by 27% and this phenotype was rescued by the transplantation of wildtype bone marrow cells. Using novel biomechanical techniques, we demonstrated that the lack of MMP-9 significantly decreased thrombus-induced loss of vein wall compliance. Biomechanical analysis of the contribution of individual structural components showed that MMP-9 affected the elasticity of the extracellular matrix and collagen-elastin fibers. Biochemical and histological analyses correlated with these biomechanical effects as thrombi of mice lacking MMP-9 had significantly fewer macrophages and collagen as compared to those of wildtype mice.

Conclusions

MMP-9 mediates thrombus-induced loss of vein wall compliance by increasing stiffness of the extracellular matrix and collagen-elastin fibers during thrombus resolution. MMP-9 also mediates macrophage and collagen content of the resolving thrombus and bone-marrow derived MMP-9 plays a role in resolution of thrombus mass. These disparate effects of MMP-9 on various aspects of thrombus illustrate the complexity of individual protease function on biomechanical and morphometric aspects of thrombus resolution.     

Model of geometrical and smooth muscle tone adaptation of carotid artery subject to step change in pressure

Recent experimental studies have shown significant alterations of the vascular smooth muscle (VSM) tone when an artery is subjected to an elevation in pressure. Therefore, the VSM participates in the adaptation process not only by means of its synthetic activity (fibronectins and collagen) or proliferative activity (hypertrophy and hyperplasia) but also by adjusting its contractile properties and its tone level. In previous theoretical models describing the time evolution of the arterial wall adaptation in response to induced hypertension, the contribution of VSM tone has been neglected. In this study, we propose a new biomechanical model for the wall adaptation to induced hypertension, including changes in VSM tone. On the basis of Hill's model, total circumferential stress is separated into its passive and active components, the active part being the stress developed by the VSM. Adaptation rate equations describe the geometrical adaptation (wall thickening) and the adaptation of active stress (VSM tone). The evolution curves that are derived from the theoretical model fit well the experimental data describing the adaptation of the rat common carotid subjected to a step increase in pressure. This leads to the identification of the model parameters and time constants by characterizing the rapidity of the adaptation processes. The agreement between the results of this simple theoretical model and the experimental data suggests that the theoretical approach used here may appropriately account for the biomechanics underlying the arterial wall adaptation.     

Effect of elastin degradation on carotid wall mechanics as assessed by a constituent-based biomechanical model

Arteries display a nonlinear anisotropic behavior dictated by the elastic properties and structural arrangement of its main constituents, elastin, collagen, and vascular smooth muscle. Elastin provides for structural integrity and for the compliance of the vessel at low pressure, whereas collagen gives the tensile resistance required at high pressures. Based on the model of Zulliger et al. (Zulliger MA, Rachev A, Stergiopulos N. Am J Physiol Heart Circ Physiol 287: H1335-H1343, 2004), which considers the contributions of elastin, collagen, and vascular smooth muscle cells (VSM) in an explicit form, we assessed the effects of enzymatic degradation of elastin on biomechanical properties of rabbit carotids. Pressure-diameter curves were obtained for controls and after elastin degradation, from which elastic and structural properties were derived. Data were fitted into the model of Zulliger et al. to assess elastic constants of elastin and collagen as well as the characteristics of the collagen engagement profile. The arterial segments were also prepared for histology to visualize and quantify elastin and collagen. Elastase treatment leads to a diameter enlargement, suggesting the existence of significant compressive prestresses within the wall. The elastic modulus was more ductile in treated arteries at low circumferential stretches and significantly greater at elevated circumferential stretches. Abrupt collagen fiber recruitment in elastase-treated arteries leads to a much stiffer vessel at high extensions. This change in collagen engagement properties results from structural alterations provoked by the degradation of elastin, suggesting a clear interaction between elastin and collagen, often neglected in previous constituent-based models of the arterial wall.     

Biomechanical response of femoral vein to chronic elevation of blood pressure in rabbits

Venous diseases like iliofemoral deep vein thrombosis and valvular dysfunction induce venous hypertension. To know the effects of the hypertension on venous mechanics, blood pressure in the left femoral vein in the rabbit was chronically elevated by the constriction of the left external iliac vein. Wall dimensions and biomechanical properties of the femoral vein were studied in vitro at 1, 2, or 4 wk after surgery. Blood pressure measured immediately before the animal was killed was significantly higher in the left femoral vein than in the sham-operated, contralateral vein. Wall thickness was increased by blood pressure elevation even at 1 wk, which restored circumferential wall stress to a control level. The stress was kept at normal up to 4 wk. Vascular tone and vascular contractility were increased by the elevation of blood pressure; however, wall elasticity and compliance were kept at a normal level. These results are very similar to those observed in hypertensive arteries, indicating that not only arteries but veins optimally operate against blood pressure elevation.     

Mechanical properties and composition of mesenteric small arteries of simulated microgravity rats with and without daily -G(x) gravitation

The aim of the present study was to evaluate the active and passive mechanical properties and wall collagen and elastin contents of mesenteric small arteries (MSAs) isolated from rats of 28-day simulated microgravity (SUS), countermeasure [S + D: SUS plus 1 h/d -G(x) to simulate intermittent artificial gravity (IAG)] and control (CON) groups. Three mechanical parameters were calculated: the overall stiffness (β), circumferential stress (σ(θ))-strain (ε(θ)) relationship and pressure-dependent incremental elastic modulus (E(inc,p)). Vessel wall collagen and elastin percentage were quantified by electron microscopy. The results demonstrate that the active mechanical behavior of MSAs differs noticeably among the three groups: the active stress-strain curve of SUS vessels is very close to the passive curve, whereas the active σ(θ)-ε(θ) curves of CON and S + D vessels are shifted leftward and display a parabolic shape, indicating that for MSAs isolated from S + D, but not those from SUS rats, the pressure-induced myogenic constriction can effectively stiffen the vessel wall as the CON vessels. The passive mechanical behavior of MSAs does not show significant differences among the three groups. However, the percentage of collagen is decreased in the wall of SUS and S + D compared with CON vessels in the following order: SUS < S + D < CON. Thus, the relationship between passive mechanical behavior and compositional changes may be complex and yet depends on factors other than the quantity of collagen and elastin. These findings have provided biomechanical data for the understanding of the mechanism of postflight orthostatic intolerance and its gravity-based countermeasure.     

A finite element model of stress-mediated vascular adaptation: application to abdominal aortic aneurysms

Despite rapid expansion of our knowledge of vascular adaptation, developing patient-specific models of diseased arteries is still an open problem. In this study, we extend existing finite element models of stress-mediated growth and remodelling of arteries to incorporate a medical image-based geometry of a healthy aorta and, then, simulate abdominal aortic aneurysm. Degradation of elastin initiates a local dilatation of the aorta while stress-mediated turnover of collagen and smooth muscle compensates the loss of elastin. Stress distributions and expansion rates during the aneurysm growth are studied for multiple spatial distribution functions of elastin degradation and kinetic parameters. Temporal variations of the degradation function are also investigated with either direct time-dependent degradation or stretch-induced degradation as possible biochemical and biomechanical mechanisms for elastin degradation. The results show that this computational model has the capability to capture the complexities of aneurysm progression due to variations of geometry, extent of damage and stress-mediated turnover as a step towards patient-specific modelling.     

A finite element model of stress-mediated vascular adaptation: application to abdominal aortic aneurysms

Despite rapid expansion of our knowledge of vascular adaptation, developing patient-specific models of diseased arteries is still an open problem. In this study, we extend existing finite element models of stress-mediated growth and remodelling of arteries to incorporate a medical image-based geometry of a healthy aorta and, then, simulate abdominal aortic aneurysm. Degradation of elastin initiates a local dilatation of the aorta while stress-mediated turnover of collagen and smooth muscle compensates the loss of elastin. Stress distributions and expansion rates during the aneurysm growth are studied for multiple spatial distribution functions of elastin degradation and kinetic parameters. Temporal variations of the degradation function are also investigated with either direct time-dependent degradation or stretch-induced degradation as possible biochemical and biomechanical mechanisms for elastin degradation. The results show that this computational model has the capability to capture the complexities of aneurysm progression due to variations of geometry, extent of damage and stress-mediated turnover as a step towards patient-specific modelling.     

Structural features of the intrinsic venous bed of the human urinary bladder

The intraorganic veins of the human urinary bladder have been studied in a vast sectional material. The veins within the organ make an enormous multilayered plexus which is differently organized in various layers of its wall. Abundant anastomoses, multiplicated ways for outflow from every layer, manifested interactions between the venous plexuses are specific for the intraorganic venous bed of the urinary bladder. The structures for an active regulating the hemomicrocirculatory blood stream are widely presented in the urinary bladder. In its every tunic certain specific morpho-functional features for organization and adaptation of the intraorganic venous bed are revealed.     

A new constitutive model for multi-layered collagenous tissues

Collagenous tissues such as the aneurysmal wall or the aorta are multi-layered structures with the mean fibre alignments distinguishing one layer from another. A constitutive representation of the multiple collagen layers is not yet developed, and hence the aim of the present study. The proposed model is based on the constitutive theory of finite elasticity and is characterized by an anisotropic strain-energy function which takes the material structure into account. The passive tissue behaviour is modelled and the related mechanical response is assumed to be dominated by elastin and collagen. While elastin is modelled by the neo-Hookean material the constitutive response of collagen is assumed to be transversely isotropic for each individual layer and based on an exponential function. The proposed constitutive function is polyconvex which ensures material stability. The model has five independent material parameters, each of which has a clear physical interpretation: the initial stiffnesses of the collagen fabric in the two principal directions, the shear modulus pertaining to the non-collagenous matrix material, a parameter describing the level of nonlinearity of the collagen fabric, and the angle between the principal directions of the collagen fabric and the reference coordinate system. An extension-inflation test of the adventitia of a human femoral artery is simulated by means of the finite element method and an error function is minimized by adjusting the material parameters yielding a good agreement between the model and the experimental data.     

Individual variability in the structure of the walls of the principal trunks of the subcutaneous veins of the lower extremities of the human fetus

Certain regional peculiarities are noted in the development process of the human principle trunks of the subcutaneous veins during antenatal period. In the fetuses of all ages the wall thickness of the subcutaneous veins is the greatest in the femur, and the middle tunic is better developed in the shin. The vein structure depends on the type of architectonics: at the magistral type (86%) the walls in the large and minor subcutaneous veins are thick with well developed smooth myocytes and connective tissue fibers; at the reticulate type (14%) the walls are thin, their elements are poorly developed. When there is mentioned varicosity of the lower extremity veins in the parents' anamnesis, in fetuses (57%) all the tunics in the venous wall develop more poorly, there is retardation in formation of smooth myocytes and in maturation of collagen fibers. This results in less amount of contractile structures in the middle tunic and optic density of collagen is less manifected.