A comparison of cell proliferation in arteries under hypertensive pressure and longitudinal stretch

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Journal of Biomechanics 2006, Vol. 39 (Suppl 1)

4491 Th, 12:15-12:30 (P42) Computational simulation of growth and remodelling G. Himpel, E. Kuhl, A. Menzel, P. Steinmann. Applied Mechanics, University

of Kaiserslautem, Kaiserslautem, Germany The essential topic of this contribution is the numerical implementation of growth and remodelling phenomena in transversely isotropic materials. Therefore we draw a distinction between to different ways of mass changes, namely density changes and volume changes. The effect of density changes can be modelled at the constitutive level, see e.g. Harrigan & Hamilton [1], by weighting the free energy function with respect to a relative density. At a constant density volume changes have to take place to attain mass changes. Following Rodriguez et al. [2] this effect can be modelled at the kinematic level, by a multiplicative split of the deformation gradient into an elastic part and a growth part, see also Himpel et al. [3]. Another aspect of this work is the remodelling of transversely isotropic materials by reorientation of the characteristic direction, see e.g. Menzel [4]. The model has been implemented into a finite program and studied by several numerical examples.

References [1] Harrigan T.P.; Hamilton J.J.: Optimality conditions for finite element simulation of adaptive bone remodeling, Int. J. Sol. Struct. 1992; 29: 2897-2906. [2] Rodriguez E.K.; Hoger A.; McCulloch A.D.: Stress-dependent finite growth in soft elastic tissues, J. Biomech. 1994; 27: 455-467. [3] Himpel G.; Kuhl E.; Menzel A.; Steinmann P.: Computational modelling of isotropic multiplicative growth, CMES 2005; 8:119-134. [4] Menzel A.: Modelling of anisotropic growth in biological tissues, Biomech. Mod. Mechan. 2005; 3: 147-171. 6310 Th, 14:00-14:15 (P44) Non-uniformity of axial and circumferential remodeling of large coronary veins in response to ligation J.S. Choy, G.S. Kassab. Department of Biomedical Engineering, University of

California, Irvine, CA, USA The pressure-induced remodeling of coronary veins is important in coronary venous retroperfusion. Our hypothesis is that the response of the large coronary veins to pressure-overload will depend on the degree of myocardial support. Eleven normal Yorkshire swine from either sex weighing 3 1 - 3 9 k g were studied. Five pigs underwent ligation of the LAD vein and six served as sham controls. The ligation of the coronary vein caused an increase in pressure intermediate to arterial and venous values. After two weeks of ligation, the animals were euthanized and the coronary vessels were perfusion-fixed with glutaraldehyde. The LAD vein was sectioned and detailed morphometric measurements were made along its length from the point of ligation near the base down to the apex of the heart. The structural remodeling of the vein was circumferentially non-uniform since the vein is partially embedded in the myocardium; it was also axially non-uniform since it is tethered to the myocardium to different degrees along its axial length. The wall area was significantly larger in the experimental group, while luminal area was significantly smaller in the same group as compared to sham controls in the proximal LAD vein. The wall thickness-to-radius ratio was also significantly larger in the experimental group in proportion to the increase in pressure. The major conclusion of this study is that the response of the vein depends on the local wall stress, which is in part, determined by the surrounding tissue. Furthermore, the geometric remodeling of the coronary vein restores the circumferential stress to the homeostatic value. 6065 Th, 14:15-14:30 (P44) Reduced axial strain disrupts normal arterial homeostasis, mechanoresponsiveness, and vasoactivity A.R. Lawrence 1, K.J. Gooch 2. 1Department ef Bioengineering and Institute

for Medicine and Engineering, Penn, Philadelphia, PA, USA, 2Department of Biomedical Engineering, Ohio State University, Columbus, OH, USA The roles of blood pressure and flow-induced shear stress in regulating vascular function, remodeling, and pathologies have been extensively studied. In addition to these forces, vessels are typically subjected to significant axial tensile forces due to the tethering of their adventitial surface to surrounding tissue, which result in stretch ratios (Z) significantly greater than 1. Yet the role of normal axial stretch and the effects of the removal of this axial stretch, as occurs in grafted vessels, remain largely unknown. To investigate the contribution of axial strain to arterial function and remodeling, we cultured porcine carotid arteries for 9 days ex vivo at normal (Z = 1.5) and reduced axial stretch ratios (Z = 1.3 and 1.0) in the presence of either normotensive (100 mmHg) or hypertensive pressures (200 mmHg). Regardless of transmural pressure, arteries lost mass when cultured with lower stretch ratios while those cultured at Z = 1.5 retained mass. This mass loss was inhibited by the MMP inhibitor GM6001, suggesting it results from an active biological process. While axial stretch was the primary determinant, pressure also affected mass at each Z, with greater average masses for the

Oral Presentations hypertensive pressure groups after perfusion. In response to hypertension, arteries exhibited positive eutrophic remodeling, but only in the presence of normal Z. Agonist-induced vasoactivity measured after culture was modulated by variations in perfusion pressure and axial strain. A combination of hypertensive pressure and reduced axial strain resulted in increases in contractility in response to norepinephrine, a possible sign of abnormal vasoactive function. Taken together these data suggest that the presence of normal axial strain is required for aspects of arterial homeostasis (e.g., maintenance of wall mass), mechanoresponsiveness (e.g., pressure-induced eutrophic remodeling) and normal vasoactivity (e.g., modulates magnitude of agonist-induced responses). 6359 Th, 14:30-14:45 (P44) A comparison of cell proliferation in arteries under hypertensive pressure and longitudinal stretch H.C. Han 1,2, Y. Lee 1,2, R.P. Vito 3, E.A. Sprague 2,3. 1Department of

Mechanical Engineering, University of Texas at San Antonio, TX, USA, 2Biomedical Engineering Program, UTSA-UTHSCSA, USA, 3School of Mechanical Engineering, Georgia Tech, Atlanta, GA, USA, 4Department of Radiology, University of Texas Health Science Center at San Antonio, TX, USA Arterial walls are subjected to a significant longitudinal stress in addition to the shear and circumferential tension produced by blood flow and pressure. The remodeling of the arterial wall under longitudinal stress remains poorly understood although the remodeling under altered flow and pressure has been well documented. The objective of this study was to examine the cell proliferation and neointima formation in arteries under elevated longitudinal stress as compared to arteries subjected to hypertensive pressure. Porcine carotid arteries were cultured for up to 7 days with ex vivo perfusion at a physiological flow rate and pressure. The perfusate used was cell culture medium DMEM supplemented with calf serum and dextran. Cell proliferation was quantified as the percent of newly proliferated cells detected by bromodeoxyuridine immunostaining over the total number of cells. The arterial wall was divided into intimal, inner medial, outer medial, and adventitial sublayers to characterize the transmural distribution of the proliferating cells. Our results showed that cell proliferation was increased in the intima and media in normal arteries cultured under a 20% stretch over their in vivo length for 7 days. Cell proliferation was slightly higher in the inner media than the outer media. The longitudinal stretch did not significantly affect the intima thickness in the arteries. However, in the endothelium-denuded arteries, cell proliferation was significantly increased in the intimal and the inner medial layers. In conclusion, the organ culture model allows accurate and consistent control of the longitudinal stretch, flow, and pressure. Cell proliferation in the longitudinally stretched arteries demonstrated different transmural distribution compared to previous data of hypertensive arteries, indicating the differences in arterial wall remodeling due to elevated longitudinal stretch and hypertensive pressure. This work was supported by a grant from NIH through MBRS SCORE program grant # S06GM08194. 4787 Th, 14:45-15:00 (P44) Mechano-control of tissue properties in cardiovascular engineered constructs R.A. Boerboom, N.J.B. Driessen, C.V.C. Bouten, F.P.T. Baaijens. Department

of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands Tissue engineering is a promising technique to create living cardiovascular replacement tissues (e.g. heart valves [1]), which are able to grow, repair and remodel in response to physical stimuli. However, creating load-bearing tissues with sufficient mechanical properties is one of the difficulties in tissue engineering. Both collagen content as well as collagen organization are important for the mechanical properties of cardiovascular tissues [2,3]. To ultimately control and predict the development of tissue composition and mechanical properties [4], it is essential to quantify the effect of mechanical conditioning on tissue formation [5]. In this study the Flexercell FX-4000T (Flexcell Int. Corp., USA) is used to study the effect of mechanical conditioning on tissue formation. The system is modified to enable long-term repeated straining of engineered tissue constructs, consisting of a degradable PGA scaffold, fibrin and myofibroblast cells, at different strain magnitudes. Well defined loading regimens in terms of strain magnitude, duration and frequency are applied to the engineered constructs. These constructs are subsequently analyzed for collagen content, cross-linking, GAG, DNA and the mechanical properties. Furthermore, the collagen architecture is studied using 2-photon microscopy, histology and TEM. Measuring these tissue properties as a function of the applied mechanical load enables us to elucidate the processes that play a role in the development of these conditioned cardiovascular engineered tissues. Differences in mechanical properties are related to the tissue composition and collagen architecture,