Rudolph L. Gleason

A Mixture Model of Arterial Growth and Remodeling in Hypertension: Altered Muscle Tone and Tissue Turnover

Hypertension results in a thickening of the arterial wall due to a net increase in wall constituents via a coordinated production and removal of smooth muscle and extracellular matrix. Although many reports address the associated changes in material properties, few models address the biomechanics of the growth and remodeling process. In this paper, we employ a new, fundamentally different approach to modeling arterial adaptation in hypertension. In particular, basic, characteristic features of hypertension are simulated using a constrained mixture model wherein individual constituents can turnover at different rates and can have different natural configurations. We show, for example, that if there is no turnover of elastin (which approximates responses in maturity), the model vessel is able to reduce an early elevation in wall stress via a thickening of the wall even though the adaptation may be suboptimal. Conversely, if all constituents can turnover completely (which may approximate late development), the model vessel can restore the state of stress and material properties to native values. Given the potential of such a model, there is a need for more data on the history of turnover of individual constituents and their individual material properties.

A Multiaxial Computer-Controlled Organ Culture and Biomechanical Device for Mouse Carotid Arteries

Much of our understanding of vascular mechanotransduction has come from studies using either cell culture or in vivo animal models, but the recent success of organ culture systems offers an exciting alternative. In studying cell-mediated vascular adaptations to altered loading, organ culture allows one to impose well-controlled mechanical loads and to perform multiaxial mechanical tests on the same vessel throughout the culture period, and thereby to observe cell-mediated vascular adaptations independent of neural and hormonal effects. Here, we present a computer-controlled perfused organ culture and biomechanical testing device designed for small caliber (50-5000 micron) blood vessels. This device can control precisely the pulsatile pressure, luminal flow, and axial load (or stretch) and perform intermittent biaxial (pressure-diameter and axial load-length) and functional tests to quantify adaptations in mechanical behavior and cellular function, respectively. Device capabilities are demonstrated by culturing mouse carotid arteries for 4 days.

A 2-D Model of Flow-Induced Alterations in the Geometry, Structure, and Properties of Carotid Arteries

Evidence from diverse investigations suggests that arterial growth and remodeling correlates well with changes in mechanical stresses from their homeostatic values. Ultimately, therefore, there is a need for a comprehensive theory that accounts for changes in the 3-D distribution of stress within the arterial wall, including residual stress, and its relation to the mechanisms of mechanotransduction. Here, however, we consider a simpler theory that allows competing hypotheses to be tested easily, that can provide guidance in the development of a 3-D theory, and that may be useful in modeling solid-fluid interactions and interpreting clinical data. Specifically, we present a 2-D constrained mixture model for the adaptation of a cylindrical artery in response to a sustained alteration in flow. Using a rule-of-mixtures model for the stress response and first order kinetics for the production and removal of the three primary load-bearing constituents within the wall, we illustrate capabilities of the model by comparing responses given complete versus negligible turnover of elastin. Findings suggest that biological constraints may result in suboptimal adaptations, consistent with reported observations. To build upon this finding, however, there is a need for significantly more data to guide the hypothesis testing as well as the formulation of specific constitutive relations within the model.

Poldip2 sustains vascular structure and function

Objective Based on previous evidence that polymerase delta interacting protein 2 (Poldip2) increases NADPH oxidase 4 (Nox4) activity in vascular smooth muscle cells (VSMC), we hypothesized that in vivo knockdown of Poldip2 would inhibit reactive oxygen species (ROS) production and alter vascular function.Objective—On the basis of previous evidence that polymerase delta interacting protein 2 (Poldip2) increases reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) activity in vascular smooth muscle cells, we hypothesized that in vivo knockdown of Poldip2 would inhibit reactive oxygen species production and alter vascular function. Approach and Results—Because homozygous Poldip2 deletion is lethal, Poldip2+/− mice were used. Poldip2 mRNA and protein levels were reduced by ≈50% in Poldip2+/− aorta, with no change in p22phox, Nox1, Nox2, and Nox4 mRNAs. NADPH oxidase activity was also inhibited in Poldip2+/− tissue. Isolated aortas from Poldip2+/− mice demonstrated impaired phenylephrine and potassium chloride–induced contractions, increased stiffness, and reduced compliance associated with disruption of elastic lamellae and excessive extracellular matrix deposition. Collagen I secretion was elevated in cultured vascular smooth muscle cells from Poldip2+/− mice and restored by H2O2 supplementation, suggesting that this novel function of Poldip2 is mediated by reactive oxygen species. Furthermore, Poldip2+/− mice were protected against aortic dilatation in a model of experimental aneurysm, an effect consistent with increased collagen secretion. Conclusions—Poldip2 knockdown reduces H2O2 production in vivo, leading to increases in extracellular matrix, greater vascular stiffness, and impaired agonist-mediated contraction. Thus, unaltered expression of Poldip2 is necessary for vascular integrity and function.

Building a functional artery: issues from the perspective of mechanics.

Despite the many successes of arterial tissue engineering, clinically viable implants may be a decade or more away. Fortunately, there is much more that we can learn from native vessels with regard to designing for optimal structure, function, and properties. Herein, we examine recent observations in vascular biology from the perspective of nonlinear mechanics. Moreover, we use a constrained mixture model to study potential contributions of individual wall constituents. In both cases, the unique biological and mechanical roles of elastin come to the forefront, especially its role in generating and modulating residual stress within the wall, which appears to be key to multiple growth and remodeling responses.

A Phenomenological Model for Mechanically Mediated Growth, Remodeling, Damage, and Plasticity of Gel-Derived Tissue Engineered Blood Vessels

Mechanical stimulation has been shown to dramatically improve mechanical and functional properties of gel-derived tissue engineered blood vessels (TEBVs). Adjusting factors such as cell source, type of extracellular matrix, cross-linking, magnitude, frequency, and time course of mechanical stimuli (among many other factors) make interpretation of experimental results challenging. Interpretation of data from such multifactor experiments requires modeling. We present a modeling framework and simulations for mechanically mediated growth, remodeling, plasticity, and damage of gel-derived TEBVs that merge ideas from classical plasticity, volumetric growth, and continuum damage mechanics. Our results are compared with published data and suggest that this model framework can predict the evolution of geometry and material behavior under common experimental loading scenarios.