Mathematical modeling of angioadaptation in response to hemodynamic and metabolic stimuli
1
$330 Journal of Biomechanics 2006, Vol. 39 (Suppl 1) Oral Presentations capillaries is designated angiogenesis. Defined morphological features that differ significantly of those of abluminal sprouting accompany shear stress- dependent angiogenesis. The endothelial cells become activated and form protrusions that invade inside the capillaries, which finally might fuse leading to splitting and intraluminal division of the microcirculation. The new vessels become subsequently covered by pericytes without significant proliferation and basement membrane remodelling. Because increases of wall shear stress might also lead to an up-regulation of endothelial nitric oxide synthase (eNOS) concentration and activity in vascular endothelial cells it seems possible that the shear stress-induction of angiogenesis depends on nitric oxide (Baum et al. Am. J. Physiol. Heart Circ. Physiol. 287: H2300-H2308, 2004). Recent research on the mutual relationship between eNOS and VEGF expression is presented and discussed. 6947 Tu, 09:15-09:30 (P17) Angioadaptation in the lung W.M. Kuebler. Institute of Physiology, Charit6 - Universitaetsmedizin Berlin, Germany Whereas the bronchial circulation has a capacity for angiogenesis quite similar to the systemic circulation, the pulmonary microvasculature appears to be relatively inert in this respect [1]. When angiogenesis occurs in the lung, e.g. in the rapidly expanding postnatal pulmonary capillary bed, it typically involves intussusception rather than sprouting of microvessels. Intussusception, i.e. "growth within itself", characterizes the splitting of microvessels by protrusion of opposing capillary walls, creation of a contact zone and later invasion of myofibroblasts and pericytes [2]. In severe pulmonary hypertension, disordered angiogenesis occurs resulting in inward proliferation of endothelial cells and formation of characteristic plexiform lesions [3]. Furthermore, mechanical and/or metabolic stress can result in remodeling of lung microvessels. Chronic hypoxia results in proliferation of vascular smooth muscle cells and fibroproliferative responses which seem to require the recruitment of circulating mesenchymal precursors [4]. Data from our own lab demonstrate that chronic pressure stress increases pulmonary vascular resistance and results in hourglass-shaped vascular narrowings. Structural and functional adaptation of endothelial cells involve polymerization of the actin cytoskeleton and impaired Ca 2+ signaling resulting in endothelial dysfunction. Thus, regulation and mechanisms of angioadaptation in the pulmonary cir- culation differ substantially from those in systemic microvessels, and play an important role in various lung diseases. References [1] W. Mitzner & E.M. Wagner, J. Appl. Physiol. 2004; 97: 1999-2004. [2] H. Kurz, P.H. Burri & V.G. Djonov, News Physiol Sci. 2003; 18: 65-70. [3] R. Tuder & N. Voelkel, Antiox Redo)( Signal 2002; 4: 833443. [4] M.G. Frid, J.A. Brunetti, D.L. Burke et al. Am J Pathol. 2006; 168: 659469. 6809 Tu, 09:30-09:45 (P17) Mathematical modeling of angioadaptation in response to hemodynamic and metabolic stimuli A.R. Pries 1, T.W. Secomb 2. 1Dept. of Physiology, CharitY-Berlin, Berlin, Germany, 2Dept. of Physiology, University of Arizona, Tucson, AZ, USA The number of structural elements in the circulatory system is extremely large. The structure of vascular elements cannot be individually controlled by genetic information. A reasonable concept is that each element reacts, through regulation of gene expression or other cellular functions, to the local conditions and stimuli that it experiences, according to a common set of genetically determined responses or 'rules' [1,3]. The continuous or repetitive application of such rules can in principle lead to development of structures that are both functionally adequate and capable of adaptation to changing conditions. Mathematical models help to understand quantitatively how vessel and network structures are controlled and coordinated by vascular responses to local stimuli: the underlying 'rules' are deduced by considering observed network properties and the constraints imposed by the requirements that the resulting system is functionally adequate, stable and robust. Structural stability and properties of terminal vascular beds can then be explained in a quantitative fashion on the basis of generic vascular responses to locally available stimuli (e.g. shear stress, circumferential wall stress, oxygen partial pressure) [2]. Such theoretical models provide a framework for understanding how structural responses of individual vessels to hemodynamic and metabolic stimuli are integrated to achieve functional microvascular networks. They can be used to predict vascular responses associated with pathophysiological processes such as hypertension or local changes of hemodynamic or metabolic conditions. References [1] Price RJ, Less JR, Van Gieson EJ, Skalak TC. Hemodynamic stresses and structural remodeling of anastomosing arteriolar networks: design principles of collateral arterioles. Microcirculation 2002; 9:111-124. [2] Pries AR, Reglin B, Secomb TW. Remodeling of blood vessels: responses of di- ameter and wall thickness to hemodynamic and metabolic stimuli. Hypertension 2005; 46: 726-731. [3] Stewart DJ, Langille BL. Tied down by shear force: role for Tie1 in postnatal vascular remodeling? Circ Res. 2004; 94: 271-272. 15.2. Molecular Mechanics of Cell Membranes and their Microvascular Consequences: A Discussion about Red Cell Mechanics at the Molecular Level 4079 Tu, 11:00-11:30 (P19) Red blood cell adhesion molecule modifications potentiated adhesion, cytokine secretion and altered endothelial cell functions J.-L. Wautier 1,2,3, W. El Nemer 2, E. Boulanger 1, N. Grossin 3, C. Le Van Kim 2, M.-P. Wautier 2 . l lnstitut National de la Transfusion Sanguine, Paris, France, 21nserm, U 665, Paris, France, 3 Universit6 Paris 7~Denis Diderot, Paris, FFa n ce Red blood cell (RBC) adhesion was found to be increased in sickle cell anemia (SS), diabetes mellitus, malaria. In SS anemia and diabetes mellitus the extent of RBC adhesion was correlated to the occurrence of vascular occlusion or the severity of vascular complication, respectively. The adhesion molecules involved in the SS RBC-endothelium interaction which were firstly described, were VLA4 (on RBCs) and vascular cell adhesion molecule (VCAM). More recently, CD239 Lu-BCAM present on RBCs was found to be increased in SS patients but also in patients with polycythemia vera and was responsible for the enhanced adhesiveness of RBCs to endothelial laminin. In addition the phosphorylation of CD239 further increased SS RBC adhesion. Glycation of hemoglobin is a marker of diabetes control and is correlated to vascular complications. More recently it was shown that RBC membrane proteins can be glycated and were implicated in the increased adhesion of RBCs to endothelium. The counter part for glycated RBC proteins is the receptor for ad- vanced glycated end products (RAGE) present on vascular endothelium. RBC binding to RAGE produced an oxidant stress and endothelial cell activation, as demonstrated by VCAM overexpression, tissue factor production Interleukin 6 and macrophage chemotactic protein-1 release. The activation of endothelial cell may also lead to apoptosis, secondary to mitochondrial alteration. These pathological situations evidenced that RBC membrane alteration may lead to endothelial cell damage and eventually to cell death. 6185 Tu, 11:30-11:45 (P20) Hybrid model of the erythrocyte membrane skeleton coupled with its lipid bilayer Q. Zhu 1, C. Vera 2, R. Asaro 1, R. Skelton 3, L.A. Sung 2. 1Department ef Structural Engineering, 2 Department of Bioengineering, 3 Department of Mechanical and Aerospace Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA, USA Biological membranes play vital roles with respect to the structural integrity and performance of cells and other biological structures. The erythrocyte membrane, a hybrid structure consisting of a lipid bilayer and a protein skeleton made mostly of spectrin and actin protofilaments, is pivotal in determining the shape and dynamical responses of the cell. During cell deformations, changes in spectrin tension and protofilament attitude may transduce mechanical forces into chemical events in the cell. In that sense, the individual junctional complex (JC) as a basic unit of the membrane skeleton may function as a sensor for mechanical deformations and/or as a controller for physiological responses. The equilibriums as well as dynamical vibrations of the JC in response to the mechanical deformation may be the underlying mechanism in a number of physiological and pathophysiological events in erythrocytes. Previously, we developed a static model to compute the equilibrium of a single unit in the membrane network under equibiaxial and anisotropic deformations using the dynamic relaxation method. Here, we report the development of a fully-coupled Direct Numerical Simulation (DNS) model of the single JC unit and the lipid bilayer. This model describes a bilayer as a nonlinear plate that could sustain bending as well as tension. The protofilament/spectrin unit is modeled as a 'moored buoy', an apparatus applied in ocean engineering. The viscous effect of the surrounding fluids is evaluated through the Oseen hydrodynamic inter- action tensor, and the thermofluctuation is incorporated by using Langevin's theory. Incorporating state-of-the-art fluid/structural algorithms, we are able to perform time-domain simulations to illustrate the dynamical behavior of the hybrid structure. This model addresses the nonlinear 3D structural dynamics of both the JC and the bilayer, the fluid-structure interactions, the interaction between the JC and the bilayer, as well as thermofluctuations. It allows us to determine the role of the skeleton-bilayer coupling, and the uncertainty caused by Brownian effects.
Transcript of Mathematical modeling of angioadaptation in response to hemodynamic and metabolic stimuli
$330 Journal o f Biomechanics 2006, Vol. 39 (Suppl 1) Oral Presentat ions
capillaries is designated angiogenesis. Defined morphological features that differ significantly of those of abluminal sprouting accompany shear stress- dependent angiogenesis. The endothelial cells become activated and form protrusions that invade inside the capillaries, which finally might fuse leading to splitting and intraluminal division of the microcirculation. The new vessels become subsequently covered by pericytes without significant proliferation and basement membrane remodelling. Because increases of wall shear stress might also lead to an up-regulation of endothelial nitric oxide synthase (eNOS) concentration and activity in vascular endothelial cells it seems possible that the shear stress-induction of angiogenesis depends on nitric oxide (Baum et al. Am. J. Physiol. Heart Circ. Physiol. 287: H2300-H2308, 2004). Recent research on the mutual relationship between eNOS and VEGF expression is presented and discussed.
6947 Tu, 09:15-09:30 (P17) Angioadaptat ion in the lung W.M. Kuebler. Institute of Physiology, Charit6 - Universitaetsmedizin Berlin, Germany
Whereas the bronchial circulation has a capacity for angiogenesis quite similar to the systemic circulation, the pulmonary microvasculature appears to be relatively inert in this respect [1]. When angiogenesis occurs in the lung, e.g. in the rapidly expanding postnatal pulmonary capillary bed, it typically involves intussusception rather than sprouting of microvessels. Intussusception, i.e. "growth within itself", characterizes the splitting of microvessels by protrusion of opposing capillary walls, creation of a contact zone and later invasion of myofibroblasts and pericytes [2]. In severe pulmonary hypertension, disordered angiogenesis occurs resulting in inward proliferation of endothelial cells and formation of characteristic plexiform lesions [3]. Furthermore, mechanical and/or metabolic stress can result in remodeling of lung microvessels. Chronic hypoxia results in proliferation of vascular smooth muscle cells and fibroproliferative responses which seem to require the recruitment of circulating mesenchymal precursors [4]. Data from our own lab demonstrate that chronic pressure stress increases pulmonary vascular resistance and results in hourglass-shaped vascular narrowings. Structural and functional adaptation of endothelial cells involve polymerization of the actin cytoskeleton and impaired Ca 2+ signaling resulting in endothelial dysfunction. Thus, regulation and mechanisms of angioadaptation in the pulmonary cir- culation differ substantially from those in systemic microvessels, and play an important role in various lung diseases.
References [1] W. Mitzner & E.M. Wagner, J. Appl. Physiol. 2004; 97: 1999-2004. [2] H. Kurz, P.H. Burri & V.G. Djonov, News Physiol Sci. 2003; 18: 65-70. [3] R. Tuder & N. Voelkel, Antiox Redo)( Signal 2002; 4: 833443. [4] M.G. Frid, J.A. Brunetti, D.L. Burke et al. Am J Pathol. 2006; 168: 659469.
6809 Tu, 09:30-09:45 (P17) Mathematical model ing o f angioadaptat ion in response to hemodynamic and metabol ic stimuli A.R. Pries 1 , T.W. Secomb 2. 1Dept. o f Physiology, CharitY-Berlin, Berlin, Germany, 2Dept. o f Physiology, University of Arizona, Tucson, AZ, USA
The number of structural elements in the circulatory system is extremely large. The structure of vascular elements cannot be individually controlled by genetic information. A reasonable concept is that each element reacts, through regulation of gene expression or other cellular functions, to the local conditions and stimuli that it experiences, according to a common set of genetically determined responses or 'rules' [1,3]. The continuous or repetitive application of such rules can in principle lead to development of structures that are both functionally adequate and capable of adaptation to changing conditions. Mathematical models help to understand quantitatively how vessel and network structures are controlled and coordinated by vascular responses to local stimuli: the underlying 'rules' are deduced by considering observed network properties and the constraints imposed by the requirements that the resulting system is functionally adequate, stable and robust. Structural stability and properties of terminal vascular beds can then be explained in a quantitative fashion on the basis of generic vascular responses to locally available stimuli (e.g. shear stress, circumferential wall stress, oxygen partial pressure) [2]. Such theoretical models provide a framework for understanding how structural responses of individual vessels to hemodynamic and metabolic stimuli are integrated to achieve functional microvascular networks. They can be used to predict vascular responses associated with pathophysiological processes such as hypertension or local changes of hemodynamic or metabolic conditions.
References [1] Price R J, Less JR, Van Gieson E J, Skalak TC. Hemodynamic stresses and
structural remodeling of anastomosing arteriolar networks: design principles of collateral arterioles. Microcirculation 2002; 9:111-124.
[2] Pries AR, Reglin B, Secomb TW. Remodeling of blood vessels: responses of di- ameter and wall thickness to hemodynamic and metabolic stimuli. Hypertension 2005; 46: 726-731.
[3] Stewart D J, Langille BL. Tied down by shear force: role for Tie1 in postnatal vascular remodeling? Circ Res. 2004; 94: 271-272.
15.2. Molecular Mechanics of Cell Membranes and their Microvascular Consequences: A Discussion about Red Cell Mechanics at the Molecular Level
4079 Tu, 11:00-11:30 (P19) Red blood cell adhes ion molecule modi f icat ions potent iated adhesion, cytokine secretion and altered endothel ia l cell functions
J.-L. Wautier 1,2,3, W. El Nemer 2, E. Boulanger 1 , N. Grossin 3, C. Le Van Kim 2, M.-P. Wautier 2 . l lnstitut National de la Transfusion Sanguine, Paris, France, 21nserm, U 665, Paris, France, 3 Universit6 Paris 7~Denis Diderot, Paris, FFa n ce
Red blood cell (RBC) adhesion was found to be increased in sickle cell anemia (SS), diabetes mellitus, malaria. In SS anemia and diabetes mellitus the extent of RBC adhesion was correlated to the occurrence of vascular occlusion or the severity of vascular complication, respectively. The adhesion molecules involved in the SS RBC-endothelium interaction which were firstly described, were VLA4 (on RBCs) and vascular cell adhesion molecule (VCAM). More recently, CD239 Lu-BCAM present on RBCs was found to be increased in SS patients but also in patients with polycythemia vera and was responsible for the enhanced adhesiveness of RBCs to endothelial laminin. In addition the phosphorylation of CD239 further increased SS RBC adhesion. Glycation of hemoglobin is a marker of diabetes control and is correlated to vascular complications. More recently it was shown that RBC membrane proteins can be glycated and were implicated in the increased adhesion of RBCs to endothelium. The counter part for glycated RBC proteins is the receptor for ad- vanced glycated end products (RAGE) present on vascular endothelium. RBC binding to RAGE produced an oxidant stress and endothelial cell activation, as demonstrated by VCAM overexpression, tissue factor production Interleukin 6 and macrophage chemotactic protein-1 release. The activation of endothelial cell may also lead to apoptosis, secondary to mitochondrial alteration. These pathological situations evidenced that RBC membrane alteration may lead to endothelial cell damage and eventually to cell death.
6185 Tu, 11:30-11:45 (P20) Hybrid model o f the erythrocyte membrane skeleton coupled with its l ipid bi layer
Q. Zhu 1 , C. Vera 2, R. Asaro 1 , R. Skelton 3, L.A. Sung 2. 1Department ef Structural Engineering, 2 Department of Bioengineering, 3 Department o f Mechanical and Aerospace Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA, USA
Biological membranes play vital roles with respect to the structural integrity and performance of cells and other biological structures. The erythrocyte membrane, a hybrid structure consisting of a lipid bilayer and a protein skeleton made mostly of spectrin and actin protofilaments, is pivotal in determining the shape and dynamical responses of the cell. During cell deformations, changes in spectrin tension and protofilament attitude may transduce mechanical forces into chemical events in the cell. In that sense, the individual junctional complex (JC) as a basic unit of the membrane skeleton may function as a sensor for mechanical deformations and/or as a controller for physiological responses. The equilibriums as well as dynamical vibrations of the JC in response to the mechanical deformation may be the underlying mechanism in a number of physiological and pathophysiological events in erythrocytes. Previously, we developed a static model to compute the equilibrium of a single unit in the membrane network under equibiaxial and anisotropic deformations using the dynamic relaxation method. Here, we report the development of a fully-coupled Direct Numerical Simulation (DNS) model of the single JC unit and the lipid bilayer. This model describes a bilayer as a nonlinear plate that could sustain bending as well as tension. The protofilament/spectrin unit is modeled as a 'moored buoy', an apparatus applied in ocean engineering. The viscous effect of the surrounding fluids is evaluated through the Oseen hydrodynamic inter- action tensor, and the thermofluctuation is incorporated by using Langevin's theory. Incorporating state-of-the-art fluid/structural algorithms, we are able to perform time-domain simulations to illustrate the dynamical behavior of the hybrid structure. This model addresses the nonlinear 3D structural dynamics of both the JC and the bilayer, the fluid-structure interactions, the interaction between the JC and the bilayer, as well as thermofluctuations. It allows us to determine the role of the skeleton-bilayer coupling, and the uncertainty caused by Brownian effects.
