Circumferential Stretch Research Articles

A novel rabbit thromboembolic occlusion model

BackgroundTo develop a preclinical thromboembolic occlusion model for studying revascularization strategies.MethodsClot analog with barium sulfate was injected into the distal aorta in 9 New Zealand white rabbits. The situation of...

Analysis of the passive biomechanical behavior of a sheep-specific aortic artery in pulsatile flow conditions

In this work, a novel numerical-experimental procedure is proposed, through the use of the Cardiac Simulation Test (CST), device that allows the exposure of the arterial tissue to in-vitro conditions, mimicking cardiac cycles generated by the heart. The main goal is to describe mechanical response of the arterial wall under physiological conditions, when it is subjected to a variable pressure wave over time, which causes a stress state affecting the biomechanical behavior of the artery wall. In order to get information related to stress and strain states, numerical simulation via finite element method, is performed under a condition of systolic and diastolic pressure. The description of this methodological procedure is performed with a sample corresponding to a sheep aorta without cardiovascular pathologies. There are two major findings: the evaluation of the mechanical properties of the sheep aorta through the above-mentioned tests and, the numerical simulation of the mechanical response under the conditions present in the CST. The results state that differences between numerical and experimental circumferential stretch in diastole and systole to distinct zones studied do not exceed 1%. However, greater discrepancies can be seen in the distensibility and incremental modulus, two main indicators, which are in the order of 30%. In addition, numerical results determine an increase of the principal maximum stress and strain between the case of systolic and diastolic pressure, corresponding to 31.1% and 14.9% for the stress and strain measurement respectively; where maximum values of these variables are located in the zone of the ascending aorta and the aortic arch.

A Mathematical Model of the Wall of a Rat Cerebral Resistance Vessel

A mathematical model of the mechanical properties of the rat small cerebral artery wall is presented. It is assumed that the active component of the stress has a circumferential direction and is a function of the concentration of the activator of smooth muscle cell contractions and circumferential and radial stretch ratios; longitudinal stretching is not considered. Calculations showed a significant decrease in both the circumferential stress and circumferential stretch ratios in the vascular wall after activation; the distribution of these values in the transmural direction became more uniform. The active component has a predominant effect on the formation of the total stress. The circumferential stress component was several times higher than the radial and longitudinal ones. The modulus of the ratio of the radial stress component to the circumferential one increased as a result of activation, and a tendency to a decrease in its value with increasing circumferential stretching was observed. Numerical analysis revealed a high sensitivity of both the radius and stress to even a small change in the values of the parameters included in the functional dependence of the stress on the concentration of the smooth muscle contraction activator.

Advances in colonic motor complexes in mice.

The primary functions of the gastrointestinal (GI) tract are to absorb nutrients, water, and electrolytes that are essential for life. This is accompanied by the capability of the GI tract to mix ingested content to maximize absorption and effectively excrete waste material. There have been major advances in understanding intrinsic neural mechanisms involved in GI motility. This review highlights major advances over the past few decades in our understanding of colonic motor complexes (CMCs), the major intrinsic neural patterns that control GI motility. CMCs are generated by rhythmic coordinated firing of large populations of myenteric neurons. Initially, it was thought that serotonin release from the mucosa was required for CMC generation. However, careful experiments have now shown that neither the mucosa nor endogenous serotonin are required, although, evidence suggests enteroendocrine (EC) cells modulate CMCs. The frequency and extent of propagation of CMCs are highly dependent on mechanical stimuli (circumferential stretch). In summary, the isolated mouse colon emerges as a good model to investigate intrinsic mechanisms underlying colonic motility and provides an excellent preparation to explore potential therapeutic agents on colonic motility, in a highly controlled in vitro environment. In addition, during CMCs, the mouse colon facilitates investigations into the emergence of dynamic assemblies of extensive neural networks, applicable to the nervous system of different organisms.

Arterial Wall Stiffening in Caveolin-1 Deficiency-Induced Pulmonary Artery Hypertension in Mice.

Pulmonary artery hypertension (PAH) is a complex disorder that can lead to right heart failure. The generation of caveolin-1 deficient mice (CAV-1-/-) has provided an alternative genetic model to study the mechanisms of pulmonary hypertension. However, the vascular adaptations in these mice have not been characterized. To determine the histological and functional changes in the pulmonary and carotid arteries in CAV-1-/- induced PAH. Pulmonary and carotid arteries of young (4-6 months old) and mature (9-12 months old) CAV-1-/- mice were tested and compared to normal wild type mice. Artery stiffness increases in CAV-1-/- mice, especially the circumferential stiffness of the pulmonary arteries. Increases in stiffness were quantified by a decrease in circumferential stretch and transition strain, increases in elastic moduli, and an increase in total strain energy at physiologic strains. Changes in mechanical properties for the pulmonary artery correlated with increased collagen content while carotid artery mechanical properties correlated with decreased elastin content. We demonstrated that an increase in artery stiffness is associated with CAV-1 deficiency-induced pulmonary hypertension. These results improve our understanding of artery remodeling in PAH.

Evaluation of the Stress-Growth Hypothesis in Saphenous Vein Perfusion Culture.

The great saphenous vein (GSV) has served as a coronary artery bypass graft (CABG) conduit for over 50years. Despite prevalent use, first-year failure rates remain high compared to arterial autograft options. Amongst other factors, vein graft failure can be attributed to material and mechanical mismatching that lead to apoptosis, inflammation, and intimal-medial hyperplasia. Through the implementation of the continuum mechanical-based theory of "stress-mediated growth and remodeling," we hypothesize that the mechanical properties of porcine GSV grafts can be favorably tuned for CABG applications prior to implantation using a prolonged but gradual transition from venous to arterial loading conditions in an inflammatory and thrombogenic deficient environment. To test this hypothesis, we used a hemodynamic-mimetic perfusion bioreactor to guide remodeling through stepwise incremental changes in pressure and flow over the course of 21-day cultures. Biaxial mechanical testing of vessels pre- and post-remodeling was performed, with results fit to structurally-motivated constitutive models using non-parametric bootstrapping. The theory of "small-on-large" was used to describe appropriate stiffness moduli, while histology and viability assays confirmed microstructural adaptations and vessel viability. Results suggest that stepwise transition from venous-to-arterial conditions results in a partial restoration of circumferential stretch and circumferential, but not axial, stress through vessel dilation and wall thickening in a primarily outward remodeling process. These remodeled tissues also exhibited decreased mechanical isotropy and circumferential, but not axial, stiffening. In contrast, only increases in axial stiffness were observed using culture under venous perfusion conditions and those tissues experienced moderate intimal resorption.

Tissue engineered vessel from a biodegradable electrospun scaffold stimulated with mechanical stretch

A tissue engineered vessel has the potential to provide an alternative small diameter vascular graft for patients with cardiovascular disease in need of surgical revascularization. In this study, a polyglycolic acid (PGA) electrospun scaffold seeded with human dermal fibroblasts was stimulated with circumferential mechanical stretch by a pulsatile perfusion system. The PGA scaffold was fabricated using a custom electrospinning set-up to co-electrospray a sacrificial polyethylene oxide microparticle to increase pore size and bulk porosity. The tissue engineered vessel exposed to circumferential mechanical stretch was compared to an engineered vessel cultured under static conditions without any mechanical stimulation. The histology cross-sections demonstrated a similar thickness of engineered vessels with mechanical stretch and static, but on Masson’s Trichrome stain there was nearly twice the amount of staining for collagen. The collagen content was quantified, and the collagen content was 60% greater in the human tissue engineered vessel exposed to mechanical stretch compared to the static vessel. The total collagen cross-linking was similar, but on a per collagen basis there was significantly more cross-linking in the static vessel over the stretch vessel. The stress-strain curve of the tissue engineered vessel with mechanical stretch demonstrated a statistically significantly greater ultimate tensile strength (UTS) of 1.86 ± 0.14 MPa (n = 6) and elastic modulus (EM) of 7.62 ± 0.39 MPa (n = 6) versus the static engineered vessel UTS of 0.31 ± 0.07 MPa (n = 5) and EM of 1.37 ± 0.21 MPa (n = 5). The primary determinant of the mechanical properties of the tissue engineered vessel correlated to the collagen content with minimal contribution of the collagen cross-linking. Therefore, the versatile properties of an electrospun scaffold are ideal in combination with a biomimetic culture system to generate a tissue engineered vessel composed of extracellular matrix suitable as a vascular graft.

Blood Flow Forces in Shaping the Vascular System: A Focus on Endothelial Cell Behavior.

The endothelium is the cell monolayer that lines the interior of the blood vessels separating the vessel lumen where blood circulates, from the surrounding tissues. During embryonic development, endothelial cells (ECs) must ensure that a tight barrier function is maintained whilst dynamically adapting to the growing vascular tree that is being formed and remodeled. Blood circulation generates mechanical forces, such as shear stress and circumferential stretch that are directly acting on the endothelium. ECs actively respond to flow-derived mechanical cues by becoming polarized, migrating and changing neighbors, undergoing shape changes, proliferating or even leaving the tissue and changing identity. It is now accepted that coordinated changes at the single cell level drive fundamental processes governing vascular network morphogenesis such as angiogenic sprouting, network pruning, lumen formation, regulation of vessel caliber and stability or cell fate transitions. Here we summarize the cell biology and mechanics of ECs in response to flow-derived forces, discuss the latest advances made at the single cell level with particular emphasis on in vivo studies and highlight potential implications for vascular pathologies.

Axial stretch regulates rat tail collecting lymphatic vessel contractions

Lymphatic contractions play a fundamental role in maintaining tissue and organ homeostasis. The lymphatic system relies on orchestrated contraction of collecting lymphatic vessels, via lymphatic muscle cells and one-way valves, to transport lymph from the interstitial space back to the great veins, against an adverse pressure gradient. Circumferential stretch is known to regulate contractile function in collecting lymphatic vessels; however, less is known about the role of axial stretch in regulating contraction. It is likely that collecting lymphatic vessels are under axial strain in vivo and that the opening and closing of lymphatic valves leads to significant changes in axial strain throughout the pumping cycle. The purpose of this paper is to quantify the responsiveness of lympatic pumping to altered axial stretch. In situ measurements suggest that rat tail collecting lymphatic vessels are under an axial stretch of ~1.24 under normal physiological loads. Ex vivo experiments on isolated rat tail collecting lymphatics showed that the contractile metrics such as contractile amplitude, frequency, ejection fraction, and fractional pump flow are sensitive to axial stretch. Multiphoton microscopy showed that the predominant orientation of collagen fibers is in the axial direction, while lymphatic muscle cell nuclei and actin fibers are oriented in both circumferential and longitudinal directions, suggesting an axial component to contraction. Taken together, these results demonstrate the significance of axial stretch in lymphatic contractile function, suggest that axial stretch may play an important role in regulating lymph transport, and demonstrate that changes in axial strains could be an important factor in disease progression.

Targeted Gold Nanoparticles as an Indicator of Mechanical Damage in an Elastase Model of Aortic Aneurysm.

Elastin is a key structural protein and its pathological degradation deterministic in aortic aneurysm (AA) outcomes. Unfortunately, using current diagnostic and clinical surveillance techniques the integrity of the elastic fiber network can only be assessed invasively. To address this, we employed fragmented elastin-targeting gold nanoparticles (EL-AuNPs) as a diagnostic tool for the evaluation of unruptured AAs. Electron dense EL-AuNPs were visualized within AAs using micro-computed tomography (micro-CT) and the corresponding Gold-to-Tissue volume ratios quantified. The Gold-to-Tissue volume ratios correlated strongly with the concentration (0, 0.5, or 10U/mL) of infused porcine pancreatic elastase and therefore the degree of elastin damage. Hyperspectral mapping confirmed the spatial targeting of the EL-AuNPs to the sites ofdamaged elastin. Nonparametric Spearman's rank correlation indicated that the micro-CT-based Gold-to-Tissue volume ratios had a strong correlation with loaded (ρ = 0.867, p-val = 0.015) and unloaded (ρ = 0.830, p-val = 0.005) vessel diameter, percent dilation (ρ = 0.976, p-val = 0.015), circumferential stress (ρ = 0.673, p-val = 0.007), loaded (ρ = -0.673, p-val = 0.017) and unloaded (ρ = -0.697, p-val = 0.031) wall thicknesses, circumferential stretch (ρ = -0.7234, p-val = 0.018), and lumen area compliance (ρ = -0.831, p-val = 0.003). Likewise, in terms of axial force and axial stress vs. stretch, the post-elastase vessels were stiffer. Collectively, these findings suggest that, when combined with CT imaging, EL-AuNPs can be used as a powerful tool in the non-destructive estimation of mechanical and geometric features of AAs.

The Effects of Prolonged Mechanical Ventilation on Structural and Material Properties of Diaphragm Arterioles

IntroductionIn skeletal muscle arterioles, cellular and vasoactive responses are influenced by the physiochemical milieu of the surrounding tissue. Understanding the mechanical properties of the blood vessel wall yields insight into vascular function in health and disease. In blood vessels, the endothelium mediates flow‐dependent vasodilation and contributes to the regulation of arterial mechanics. Prolonged mechanical ventilation (MV)(>6 h) results in large, time‐dependent reductions in diaphragmatic blood flow and impaired endothelium‐dependent (and ‐independent) vasodilation of first‐order (1A) medial costal diaphragm arterioles. The purpose of this investigation was to determine if the severe reductions in diaphragmatic blood flow (and shear‐stress) with MV impair the structural and material properties (i.e. increased stress/stretch relation and/or circumferential stretch) of 1A arterioles from the medial costal diaphragm.MethodsFemale Sprague‐Dawley rats (~5 mo) were randomly divided into two groups, spontaneous breathing (SB, n = 6) and prolonged MV (6 h MV, n =5). Following SB and 6 h MV, 1A medial costal diaphragm arterioles (~200 μm diameter, ~2 mm in length) were isolated and cannulated. After cannulation, vessels were adjusted to a fixed length (L, 1.5 mm) and pressurized. Vessels that exhibited no leaks were subjected to a step‐wise passive‐pressure diameter test (0–140 cmH2O) in calcium‐free Ringer’s solution, at a single fixed axial length (L). Inner diameter (μm) and wall thickness (μm) were measured at each pressure step and used to calculate wall: lumen ratio, incremental distensibility (%/mmHg), Cauchy‐stress (μ), and circumferential stretch (λθ).ResultsFollowing 6 h MV, in the undeformed condition (0 mmHg) the wall: lumen ratio was significantly smaller compared to SB (1.04 ±0.21vs. 2.60 ±0.40; p<0.05). There were no differences in incremental distensibility (%/mmHg) and the stress/stretch (μvs λθ) relation between groups (p>0.05). At every pressure step, circumferential stretch (λθ; undeformed radius (r)/current deformed radius (R)) was significantly increased with 6 h MV versus SB (p<0.05).ConclusionDespite no change in the distensibility and structural behavior (stress/stretch) of resistance vessels from the medial costal diaphragm, prolonged MV resulted in altered material properties (i.e. elevated circumferential stretch (λθ)) of medial costal diaphragm arterioles. Increased circumferential stretch can enhance superoxide generation in the endothelium and vascular smooth muscle cells. Therefore, elevated circumferential stretch of 1A diaphragm arterioles in combination with the severe reductions in blood flow may, in part, explain the previously demonstrated vascular dysfunction in the diaphragm following MV.Support or Funding InformationSupported by: NIH HL137156‐01A1

Investigation of the Influence of Smooth Muscle Contractions on the Properties of the Wall of a Small Arterial Vessel

The plane problem of the effect of contractions of smooth muscle cells in the wall of a resistance vessel under the action of transmural pressure on the radius and the distribution of stresses in the vascular wall is considered. It is assumed that in the inactivated state the vessel wall is hyperelastic, and the contraction of smooth muscle cells as a result of activation contributes to the circumferential stress alone. Based on the model and published experimental data, a functional dependence of the active stress on the concentration of the activator of smooth muscle contraction is obtained. Calculations show that the total stress in the wall is determined mainly by the active component. With increasing pressure, contractions of smooth muscle cells lead to decrease in stresses, while the pattern of the distribution of circumferential stresses changes. The circumferential stretch ratios also decrease with activation and their distribution becomes more homogeneous. In both passive and active vessels, the modulus of the ratio of the radial to circumferential stress decreases with increase in tension, this ratio being several times greater in the active vessel than in the passive one.

Mechanical and structural changes in human thoracic aortas with age

Aortic mechanical and structural characteristics have profound effects on pathophysiology, but many aspects of physiologic stress-stretch state and intramural changes due to aging remain poorly understood in human tissues. While difficult to assess in vivo due to residual stresses and pre-stretch, physiologic stress-stretch characteristics can be calculated using experimentally-measured mechanical properties and constitutive modeling. Mechanical properties of 76 human descending thoracic aortas (TA) from 13 to 78-year-old donors (mean age 51±18 years) were measured using multi-ratio planar biaxial extension. Constitutive parameters were derived for aortas in 7 age groups, and the physiologic stress-stretch state was calculated. Intramural characteristics were quantified from histological images and related to aortic morphometry and mechanics. TA stiffness increased with age, and aortas became more nonlinear and anisotropic. Systolic and diastolic elastic energy available for pulsation decreased with age from 30 to 8 kPa and from 18 to 5 kPa, respectively. Cardiac cycle circumferential stretch dropped from 1.14 to 1.04, and circumferential and longitudinal physiologic stresses decreased with age from 90 to 72 kPa and from 90 to 17 kPa, respectively. Aortic wall thickness and radii increased with age, while the density of elastin in the tunica media decreased. The number of elastic lamellae and circumferential physiologic stress per lamellae unit remained constant with age at 102±10 and 0.85±0.04 kPa, respectively. Characterization of mechanical, physiological, and structural features in human aortas of different ages can help understand aortic pathology, inform the development of animal models that simulate human aging, and assist with designing devices for open and endovascular aortic repairs. Statement of significanceThis manuscript describes mechanical and structural changes occurring in human thoracic aortas with age, and presents material parameters for 4 commonly used constitutive models. Presented data can help better understand aortic pathology, inform the development of animal models that simulate human aging, and assist with designing devices for open and endovascular aortic repairs.

Fluid structure interaction modeling of aortic arch and carotid bifurcation as the location of baroreceptors

Hemodynamic forces play an important role in both physiological function and pathological conditions of the cardiovascular system. These forces are sensed by the mechanoreceptors of the vessel wall to give the proper response for homeostasis maintenance. Baroreceptors are a kind of mechanoreceptors which are sensitive to the abnormal stretch magnitudes. Therefore to assess the function of these receptors, predicting the stress and stretch distributions induced by the hemodynamic field to the arterial wall is crucial in the barosensitive regions.In this study, 3D patient-specific models of the aortic arch and carotid bifurcation which are the common positions of the baroreceptors are presented. Geometries were reconstructed based on MRI images and pulsatile numerical analysis was performed considering fluid-structure interaction. The hemodynamic field containing the velocity, WSS and pressure distributions was discussed in the fluid domain and the stress and deformation fields were analyzed in the solid domain. Comparing the temporal variations of pressure and circumferential stretch at the two barosensitive regions, the circumferential stretch is proposed as the criterion for quantifying the function of baroreceptors.

Integrating Flexible Electrochemical Sensor into Microfluidic Chip for Simulating and Monitoring Vascular Mechanotransduction.

As an interface between the blood flow and vessel wall, endothelial cells (ECs) are exposed to hemodynamic forces, and the biochemical molecules released from ECs-blood flow interaction are important determinants of vascular homeostasis. Versatile microfluidic chips have been designed to simulate the biological and physiological parameters of the human vascular system, but in situ and real-time monitoring of the mechanical force-triggered signals during vascular mechanotransduction still remains a significant challenge. Here, such challenge is fulfilled for the first time, by preparation of a flexible and stretchable electrochemical sensor and its incorporation into a microfluidic vascular chip. This allows simulating of in vivo physiological and biomechanical parameters of blood vessels, and simultaneously monitoring the mechanically induced biochemical signals in real time. Specifically, the cyclic circumferential stretch that is actually exerted on endothelium but is hard to reproduce in vitro is successfully recapitulated, and nitric oxide signals under normal blood pressure, as well as reactive oxygen species signals under hypertensive states, are well documented. Here, the first integration of a flexible electrochemical sensor into a microfluidic chip is reported, therefore paving a way to evaluate in vitro organs by built-in flexible sensors.

A meniscus fingering instability in viscoelastic fluids

We report experiments where a viscoelastic fingering instability develops at the free interface between air and a model viscoelastic fluid confined in a Hele-Shaw cell. The fluid is symmetrically stretched with constant velocity along two opposite directions, leading to the inflation of a two-dimensional air bubble growing from a millimetric centered hole. The instability is observed when the circumferential stretch of the inflating bubble reaches a threshold that depends on the viscoelastic properties of the fluid through the ratio of the material relaxation time to the time elapsed before the fingers start to develop. The critical stretch of the bulk fingering instability of a stretchable elastic solid [B. Saintyves, O. Dauchot, and E. Bouchaud, “Bulk elastic fingering instability in Hele-Shaw cells,” Phys. Rev. Lett. 111, 047801 (2013)] is recovered for large values of this ratio.

Micromechanically-motivated analysis of fibrous tissue

Collagen fibers are the main load bearing component in fibrous tissues. Systematic analyses of their structure and orientation are thus crucial for the development of material models that enable to predict the mechanical tissue response. To this end, biaxial tests at different stretch ratios were performed on two tissue samples of the medial layer extracted from a human aorta. The tissues were loaded in the circumferential and axial directions simultaneously. We develop here a micromechanical model which is based on structural parameters of collagen fibers that were extracted from second-harmonic generation images of the two samples. The tissue is modeled as a periodic six-layered laminate in which the individual layers are treated as periodic fibrous structures with one family of fibers. We make use of the Hill-Mandel theory in the context of periodic homogenization to determine the overall mechanical tissue response. Both the analytical and numerical models are able to capture the overall mechanical response of the two tissue samples using a straightforward representation of the tissue structure together with a limited set of material parameters. Up to 10% of strains the model captures the almost linear response of both tissue samples. Beyond that stretch level the stiffening of the tissues becomes more evident, especially in the circumferential direction. In cases where the axial stretch is larger than the circumferential stretch the predictions are somewhat stiffer, while a very good agreement is obtained when the circumferential stretch is dominant. The stiffening of one tissue sample was substantially larger than the other, implying that higher-order stiffening mechanisms may kick in at larger strains. Our sensitivity analyses reveal that the parameters of the material model and the fiber dispersion have a minor effect on the tissue response. The novel modeling approach has the potential to reduce the need of time-consuming experimental data of the mechanical behavior of fibrous tissues.

Generation and Initial Characterization of 3D Cortical Collecting Ducts (CCDs)‐on‐a‐Chip

Hydrodynamic forces, including fluid shear stress (FSS), circumferential stretch and drag/torque on apical cilia, regulate ion transport in the CCD of the kidney. Studies aimed at examining pathways and regulation of transepithelial transport in this nephron segment are largely limited to experiments in 2D cell culture monolayers, while renal tubular epithelia grown in their native 3D geometry provide a more physiologically relevant environment. Cell doming is a characteristic unique to epithelial cell monolayers and has previously been described by others to reflect cellular differentiation and vectorial transport of salt and water. We describe the doming characteristics of cells grown in a novel in vitro 3D microphysiological model that recapitulates the in vivo geometry of the CCD. 3D CCD‐like tubules were generated using a pin pullout technique to generate a 500 μm hollow lumen through a fibrin/gelatin extracellular matrix (ECM) enclosed within a polydimethylsiloxane scaffold. The lumen was seeded with mpkCCD cells x 24 hr then continuously perfused with cell culture media via a peristaltic pump in a closed loop circuit at a unidirectional FSS of 0.1 dyn/cm2. By 7 d of culture/perfusion, a confluent monolayer of cells lined the channel. Epithelial integrity was demonstrated using widefield microscopy by retention of a continuously perfused 70 kDa FITC‐dextran (25 μM) in the lumen for 5 hr. Confocal microscopy of 50 μm sections of tubules labeled with target‐specific antibodies revealed ENaC, Na‐K‐ATPase and laminin expression. Cell doming was observed after about 30 minutes of stopping flow (no flow) in all tubules. We quantitatively measured doming characteristics by live‐cell differential interference contrast video microscopy in a 1 mm tubule segment at the inlet of each chip after a 1 hr period of no flow, in the absence (control) or presence of 10 μM benzamil (BZ), an inhibitor of ENaC. Interestingly, domes were observed in only 1 of the benzamil treated tubules. Dome dimensions were measured and volume was estimated using the formula for a segment of a sphere. Data are presented as X ± SEM from individual experiments. Significance of differences was tested by unpaired Student t‐test and statistical significance was defined as P values <0.05. The mean dome volume was ~3.1 ± 0.5 nl in 3 tubules in the absence vs. ~0.04 ± 0.01 nl in the 1 tubule that demonstrated doming in the presence of BZ (P=0.01). In summary, we generated and initially characterized a 3D CCD‐on‐achip that promises to provide a relevant model for studying transport physiology and addressing a variety of clinically important questions. The mechanism(s) underlying dome formation remains to be determined.Support or Funding InformationNIH grants T32DK007757 (JLR), R01DK038470 (LMS) and the NIDDK (Re)Building A Kidney Consortium grant U01DK107350 (LMS). Microscopy was performed at the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mechanosensing and Mechanoregulation of Endothelial Cell Functions.

Vascular endothelial cells (ECs) form a semiselective barrier for macromolecules and cell elements regulated by dynamic interactions between cytoskeletal elements and cell adhesion complexes. ECs also participate in many other vital processes including innate immune reactions, vascular repair, secretion, and metabolism of bioactive molecules. Moreover, vascular ECs represent a unique cell type exposed to continuous, time-dependent mechanical forces: different patterns of shear stress imposed by blood flow in macrovasculature and by rolling blood cells in the microvasculature; circumferential cyclic stretch experienced by the arterial vascular bed caused by heart propulsions; mechanical stretch of lung microvascular endothelium at different magnitudes due to spontaneous respiration or mechanical ventilation in critically ill patients. Accumulating evidence suggests that vascular ECs contain mechanosensory complexes, which rapidly react to changes in mechanical loading, process the signal, and develop context-specific adaptive responses to rebalance the cell homeostatic state. The significance of the interactions between specific mechanical forces in the EC microenvironment together with circulating bioactive molecules in the progression and resolution of vascular pathologies including vascular injury, atherosclerosis, pulmonary edema, and acute respiratory distress syndrome has been only recently recognized. This review will summarize the current understanding of EC mechanosensory mechanisms, modulation of EC responses to humoral factors by surrounding mechanical forces (particularly the cyclic stretch), and discuss recent findings of magnitude-specific regulation of EC functions by transcriptional, posttranscriptional and epigenetic mechanisms using -omics approaches. We also discuss ongoing challenges and future opportunities in developing new therapies targeting dysregulated mechanosensing mechanisms to treat vascular diseases. © 2019 American Physiological Society. Compr Physiol 9:873-904, 2019.

The effect of endothelial nitric oxide synthase on the hemodynamics and wall mechanics in murine arteriovenous fistulas

Creation of a hemodialysis arteriovenous fistula (AVF) causes aberrant vascular mechanics at and near the AVF anastomosis. When inadequately regulated, these aberrant mechanical factors may impede AVF lumen expansion to cause AVF maturation failure, a significant clinical problem with no effective treatments. The endothelial nitric oxide synthase (NOS3) system is crucial for vascular health and function, but its effect on AVF maturation has not been fully characterized. We hypothesize that NOS3 promotes AVF maturation by regulating local vascular mechanics following AVF creation. Here we report the first MRI-based fluid-structure interaction (FSI) study in a murine AVF model using three mouse strains: NOS3 overexpression (NOS3 OE) and knockout (NOS3−/−) on C57BL/6 background, with C57BL/6 as the wild-type control (NOS3+/+). When compared to NOS3+/+ and NOS3−/−, AVFs in the OE mice had larger lumen area. AVFs in the OE mice also had smoother blood flow streamlines, as well as lower blood shear stress at the wall, blood vorticity, inner wall circumferential stretch, and radial wall thinning at the anastomosis. Our results demonstrate that overexpression of NOS3 resulted in distinct hemodynamic and wall mechanical profiles associated with favorable AVF remodeling. Enhancing NOS3 expression may be a potential therapeutic approach for promoting AVF maturation.