$374 Journal of Biomechanics 2006, Vol. 39 (Suppl 1) Oral Presentations

glycocalyx, raising l~g, and limiting sustained reabsorption. The perfusate in five microvessels of rat mesentery was 50mg/ml and the microvessel pressure was 10cm H20. The superfusate contained albumin at 20mg/ml (average interstitial protein concentration, 40% of plasma concentration). The mesothelium was opened 100 microns on both sides of each microvessel to clamp interstitial protein concentration at the superfusate concentration at this site, and to provide a sink for albumin diffusion from the interstitium. Perfusion conditions favoring steady reabsorption were maintained for up to 10 minutes and transvascular flows measured at intervals of 1-3 minutes. Reabsorption was measured in all microvessels. A simplified (1D) version of the 3D model for water and solute described in the reference above showed that, although there can be no steady reabsorption if l~t is determined only by transport of water and solute across the endothelial barrier (Michel and Phillips, J Physiol 388: 421, 1987), reabsorption is possible when a sink for plasma proteins in the interstitium maintains concentration gradients and an albumin diffusion flux from beneath the glycocalyx is large enough to overcome protein accumulation by convection. Supported by NIH HL 44485.

6451 Tu, 12:00-12:15 (P20) Intravital microcopic studies of resistance arteries as a model for the investigation of endothelial-dependent vasorelaxation in vivo H.-A. Lehr, S. Sch~fer. Institut Universitaire de Pathologie, Centre Hospitalier, Universitaire Vaudois (CHUV), Lausanne, Switzerland

A plethora of information exists concerning the mechanisms anmd mediator systems of endothelial-dependent vasorelaxation. In particular, the generation and action of NO - and lately the possibilities to affects these sytems by pharmacological and dietary mechanisms has been a focus of intensive research. Most of these studies have been performed either in vitro or else ex vive using large conductance vessels. Yet, blood pressure is much rather regulated at the level of resistance arterioles than at the level of these large caliber conductance vessles and several lines of evidence suggest that these exist major differences concerning the regulation of vascular tone between these vessel segmentrs. In collaboration with the teams of Ulrich Pohl (Physiology) and Ulrich F6rstermann (Pharmacology), our group has used the dorsal skinfold chamber model in hamsters and wildtype as well as genetically modified mice to study the response of resistance arterioles to NO dependent and NO independent agents. For that purpose, we have chronically implanted observation chambers into the dorsal skinfold of experimental animals and studied the response of precapillary arterioles (30-70 ~tm diameter) to topical superfusion with acetylcholine (stimulating endogeneous NO synthesis) or SNAP (a source of exogenous NO). We will present a selection of data on the effects of various pathophysiological conditions on endothelial-dependent vasorelaxation of these resistance arterioles, such as anesthesia (DeWit et al., 1999), steroid-induced hypertension (Wallerath et al., 1999; Sch~fer et al., 2004), hypercholesterolemia (Li et al., 2005) and will demonstrate the poten- tial restoration of dysfunctional vasorelaxtation by pharmacological (i.e. NOS stimulating drugs) and dietary (i.e. arginine, vitamin C, alcoholic beverages) manipulations.

6284 Tu, 12:15-12:30 (P20) Theoretical models for flow regulation based on the length-tension characteristics of vascular smooth muscle T.W. Secomb 1 , B.E. Carlson 2. 1Department of Physiology, University of Arizona, Tucson AZ, USA, 2Department of Bioengineering, University of Washington, Seattle, WA, USA

A theoretical model is developed to describe the myogenic and shear- dependent responses of arterioles to changes in intravascular pressure and flow rate, based on the active and passive length-tension characteristics of vas- cular smooth muscle (VSM). The vessel wall is represented mechanically as a nonlinear passive component in parallel with an active contractile component. The level of active VSM tone is assumed to have sigmoidal dependence on both wall tension and wall shear stress. Model parameters are obtained from experimental data obtained with isolated arterioles. This model is used to an- alyze the contributions of myogenic and shear-dependent vascular responses to autoregulation and metabolic regulation of blood flow. The vasculature is divided into several vascular levels, each represented by a set of identical vessel segments connected in parallel. To simulate autoregulation, mean arterial pressure is varied from 60 to 150 mmHg. With both responses present, the predicted flow increase over this range is reduced by 80% compared to the increase without these responses, indicating strong autoregulation. To simulate metabolic regulation, the conductance of small arteriolar segments is assumed to increase by a factor of 16 in response to local metabolic signals. With myogenic and shear responses in the upstream arteriolar segments, the predicted increase in flow is almost three-fold higher than when the myogenic and shear responses are suppressed. The results show that the myogenic and shear responses contribute significantly to autoregulation and to metabolic

regulation amplification. However, the predicted responses are not as strong as seen experimentally, suggesting that other mechanisms, particularly the upstream conducted response, are also needed for effective autoregulation and metabolic regulation of blood flow. Supported by NIH Grant HL070657.

19.2. Transport across Blood Vessel Walls I

7782 Tu, 14:00-14:15 (P23) Changes with age in the pattern of high-permeability foci in the rabbit aortic endothelium near branch points S.G. Cremers, P.D. Weinberg. Department of Bioengineering, Imperial College, London, UK

The non-uniform distribution of atherosclerotic lesions within the arterial sys- tem may be caused by local variation in macromolecule transport between blood and the arterial wall. Previous work has shown that lesions develop downstream of side branches in the aorta of hypercholesterolaemic rabbits. Prior to the development of lesions, these regions show an elevated uptake of plasma macromolecules. Some studies have suggested that the elevated uptake can be explained in part by a high frequency of focal sites of elevated permeability ("hotspots"), which may in turn reflect the presence of damaged, dividing or dying endothelial cells. We have recently shown that the distribution of lesions in rabbits is in fact re- lated to age; although lesions occur downstream of branch points in immature animals, they occur more frequently at the sides of branches at later ages. This switch parallels a similar age-related change in lesion pattern in the human aorta. We have further shown that macromolecule uptake by the rabbit aortic wall also shows these age-related changes in pattern. Here we investigated whether the frequency of hotspots shows these changes too. Immature and mature conscious male New Zealand White rabbits (n = 10) fed a normal diet were administered Evans' Blue Dye (EBD)-Iabelled albumin intravenously. Animals were given heparin 8 minutes later, and an overdose of pentobarbitone after a further 2 minutes. Aortas were fixed in situ at physiological pressure and excised, and the distribution of EBD fluorescence around the origins of intercostal arteries was imaged en face by confocal microscopy. Hotspots occurred most frequently near the downstream margin of branch ostia in immature animals, but at the sides of ostia in mature animals. This finding strengthens the view that hotspots play a causal role in arterial lipid deposition in rabbits and may also be relevant to the development of atherosclerosis in human arteries. Supported by the British Heart Foundation

5036 Tu, 14:15-14:30 (P23) A model of intimal hyperplasia & mechanical forces

M.E. Goodman 1 , N.A. Hill 2, X.'~ Luo 2. 1Department ef Mechanical Engineering, The University of Sheffield, Sheffield, UK, 2Department of Mathematics, The University of Glasgow, Glasgow, UK

Lipid and Lipoprotein metabolism have been the focus of intense research over the last 25 years for their part in the pathogenesis of Atherosclerosis. The precise underlying causes and progression of the disease is complex and poorly understood. Homodynamic forces, especially shear stress acting on the arterial wall are thought to play a key role in the disease by modifying the permeability of endothelium cells (which line the vessel wall) to LDL (Low Density Lipoprotein). Oxidative modification of LDL within the Intima is known to be significant in triggering the development of atherosclerotic lesions. We present a new model linking blood flow, shear dependent endothelium permeability and intimal thickening of the arterial wall. Key concepts are that the intimal layer swells in response to the presence of excess oxidised cholesterol in foam cells, this swelling disturbs blood flow, affecting endothelial permeability. These changes produce a feedback mechanism. LDL transport is by advection and diffusion, the distribution of LDL at each time step is assumed to be quasi-steady. Initially we consider a section of uniform axisymmetric artery, imposing an initial 'hotspot' of permeability locally enhances the influx of LDL, triggering the development of a lesion shaped bump. We are interested in how this bump shape changes over time, its effect on wall shear stress, influx rates of LDL and the sensitivity of these processes to oxidation parameters. Preliminary results will be presented showing the influence of wall thickness and oxidation rates on the accumulation of LDL and oxidized LDL. Physiologically realistic behaviour will be used to discuss model parameters and the observations made about wall shape changes. This research is novel as it is the first time interactions between intimal hyperplasia, oxidation, shear stress and endothelial permeability have been coupled together in a single model.