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Effects of shear stress on endothelial activation and vascular inflammation
Available online at www.sciencedirect.com
Biomedicine & Pharmacotherapy 62 (2008) 503e512 www.elsevier.com/locate/biopha
Abstracts
The vascular endothelium: basic and clinical aspects 1 The vascular endothelum: Structural, functional and pathophysiological aspects Axel R. Pries Dept. of Physiology, Charite´ Universita¨tsmedizin Berlin and DHZB Berlin, Germany The endothelium is an organ with a large surface (w 350m2) and a comparatively small total mass (w110g) which plays a central role for regulation of perfusion, fluid and solute exchange, haemostasis and coagulation, inflammatory responses, vasculogenesis and angiogenesis. Between vessels and organs, the endothelium differs in its morphology ("continuous", "fenestrated" or "discontinuous") and functional properties (e.g permeability, expression of surface molecules, responses to hemodynamic forces, pacemaker cells). For example, there are marked structural and functional differences between the endothelial lining of the lung and the brain. In the pulmonary endothelium, the level of adhesion molecule expression is constitutively high, allowing to maintain a large pool of marginated leukocytes. Endothelial cells in the brain are characterized by the lack of fenestrations and an elaborate system of tight junctions limiting and controlling exchange with the interstitial compartment. A central component of endothelial function in many organs is the release of active substances in response to chemical agonists and to hemodynamic forces, including NO, prostacyclin and EDHF (endothelium derived hyperpolarizing factor). These substances control vascular tone, but also structural vascular adaptation, proliferation, and inflammation. In recent years, it became increasingly clear that the luminal endothelial surface is covered with a gel-like layer exhibiting a thickness in the range of 0.5 to 1 mm. This layer has been named endothelial surface layer (ESL) and is much thicker as compared to the so called glycocalyx which consists of proteoglycanes and glycoproteins anchored in the endothelial
plasma membrane (typical thickness of about 50-100mm). While the composition of the ESL still remains largely elusive, adsorbed plasma proteins and hyaluronan seem to be essential. Due to its wide ranging roles for fluid exchange, flow resistance, oxygen transport, vascular control, coagulation, inflammation, and atherosclerosis, the ESL will be a relevant focus for future studies in endothelial function. E-mail address: [email protected]
2 Effects of shear stress on endothelial activation and vascular inflammation Paul C. Evans BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, UK Atherosclerosis is a chronic lipid-driven inflammatory disease of arteries that causes heart attack or stroke. Early lesions (fatty streaks) contain monocytes and T lymphocytes which are recruited from the circulation to activated vascular endothelial cells (EC) which express adhesion molecules (e.g. Eselectin, VCAM-1) and chemokines (e.g. IL-8, MCP-1) at their surface. This process relies on dual activation of NFkB and MAP kinase e AP-1 signaling pathways which leads to transcriptional activation of pro-inflammatory genes. Hemodynamics play a central role in regulating vascular inflammation and atherosclerosis which occurs predominantly at branches and bends of the arterial tree that are exposed to relatively low or re-circulating blood flow. In contrast, regions of the arterial tree with uniform geometry that are exposed to high rates of unidirectional flow are protected from inflammation and atherosclerosis. Blood flow exerts shear stress (mechanical drag) at the interface between blood and the endothelial layer, where it induces a shearing deformation of the endothelial cells. Thus protected regions of the arterial tree with uniform geometry are exposed to high
Abstracts / Biomedicine & Pharmacotherapy 62 (2008) 503e512
504
shear stress, whereas susceptible regions, e.g. arches and branches, are exposed to low / oscillatory shear. Shear stress regulates vascular inflammation and atherosclerosis by altering the physiology of endothelial cells (EC), which detect shear stress via a tri-molecular complex expressed at their surface. High shear stress suppresses EC activation by inhibiting pro-inflammatory NF-kB and MAP kinase e AP-1 signaling via mechanisms that involve the activation of KLF2 and Nrf2 transcription factors. In contrast, low and oscillatory shear enhances endothelial activation via activation of MAP kinase e AP-1 and NF-kB pathways. These mechanisms are likely to contribute to the focal distribution of atherosclerotic lesions and could potentially be exploited to design novel therapeutic strategies to protect susceptible regions of the arterial tree from inflammation and atherosclerosis. E-mail address: [email protected]
3 Leukocyte-Endothelial Interactions with Respect to the Adhesion Cascade Dr Victoria Ridger Cardiovascular Research Unit, School of Medicine and Biomedical Sciences,University of Sheffield, UK Leukocyte recruitment to the site of injury and inflammation occurs via a sequence highly regulated events, collectively known as the adhesion cascade. They are characterised as capture, rolling, slow rolling, crawling, adhesion and extravasation. At each step, leukocytes interact with the endothelium through adhesion molecules; the selectins and their ligands regulate the first contact events and rolling whereas the integrins are involved in the later stages. Not only do these molecules control the physical interactions between leukocytes and endothelial cells, but they also are involved in signalling and preparing the leukocyte for the subsequent steps in the cascade. The onset of inflammation increases the expression and alters the avidity of these adhesion molecules on both the leukocytes and the endothelium, increasing the adhesive environment. Marginated leukocytes make initial contact with endothelial cells through interaction of L- (on leukocyte) or P- (on endothelial cells) selectins with their respective ligands. Rolling then occurs through a series of bond formations at the leading edge and breakages at the trailing edge of the leukocyte. The next stage of the cascade is slow rolling, mediated by E-selectin, observed after longer periods of endothelial stimulation. Slow rolling is thought to play a role in prolonging the exposure of rolling leukocytes to chemokines. Rolling also triggers cell signalling events thought to prepare the cell for the next step of ‘‘firm’’ adhesion. Chemokines are involved in the transition of rolling into firm adhesion and in the shedding of L-selectin from the surface of leukocytes. Firm adhesion is known to be highly dependent on b2 integrins and their ligands, members of the immunoglobulin superfamily. Once firmly adherent, leukocytes crawl towards endothelial-endothelial cell junctions via these same interactions. Transendothelial migration is
generally thought to occur in an intercellular manner and is mediated by integrin PECAM-1, ICAM-2, JAM-A and CD99. However this latter stage is not as well characterised. The understanding of the adhesion cascade and the multiple steps involved in leukocyte recruitment is essential for the development of effective, novel therapies for inflammatory diseases. E-mail address: [email protected]
4 Vascular device interaction with the endothelium Mark Atherton 1, Ashraf W Khir 1, Marco Cavazzuti 2, Giovanni Barozzi 2, & Michael Collins 1 1
School of Engineering and Design, Brunel University, West London, UK 2 Dipartminto di Ingegneria Meccanica e Civile, Universita` di Modena e Reggio Emilia, Italy Cerebral stents and Intra Aortic Balloon Pumps (IABP) are examples of mechanical devices that are inserted into arteries to restore flows to clinically healthy states. The stent and the IABP ‘correct’ the arterial flow by static dilation and by cyclical occlusion respectively. As this presentation shows, these functions are effectively modelled by current engineering practice. As interventions however, by their very nature they involve physical contact between a non-biological structure and the sensitive endothelial surface. The possible damage to the endothelium is not currently well addressed and we also consider this issue. Cerebral stents generally have two primary clinical objectives: to mechanically dilate a stenosed artery and to have minimal detrimental impact upon local blood flow characteristics. These objectives are well served at the arterial scale as these devices are evidently effective in opening up diseased arteries and restoring vital flows. However, at the near-wall micro-scale the picture is less satisfactory, as thin stent wires apply stresses to the endothelium and glycocalyx and the local flow is disturbed rather than being ideally streamlined. This causes further interaction with this endothelium topography. Wall Shear Stress (WSS) is the measure commonly used to indicate the interaction between fluid and wall but it is a broad brush approach that loses fidelity close to the wall. We will present simulation results of blood flow through a stented cerebral saccular aneurysm under these limitations of WSS. The Intra Aortic Balloon Pump (IABP) is a widely used temporary cardiac assist device. The balloon is usually inserted from the iliac artery, advanced in the aorta until it reaches the desired position; with its base just above the renal bifurcation and the tip approximately 10cm away from the aortic valve. The balloon is inflated and deflated every(1:1), every other- (1:2) or every second (1:3) cardiac cycle. Balloon inflation, which takes place during early diastole, causes an increase in the pressure of the aortic root which leads to an increase in coronary flow. Balloon deflation which
Biomedicine & Pharmacotherapy 62 (2008) 503e512 www.elsevier.com/locate/biopha
Abstracts
The vascular endothelium: basic and clinical aspects 1 The vascular endothelum: Structural, functional and pathophysiological aspects Axel R. Pries Dept. of Physiology, Charite´ Universita¨tsmedizin Berlin and DHZB Berlin, Germany The endothelium is an organ with a large surface (w 350m2) and a comparatively small total mass (w110g) which plays a central role for regulation of perfusion, fluid and solute exchange, haemostasis and coagulation, inflammatory responses, vasculogenesis and angiogenesis. Between vessels and organs, the endothelium differs in its morphology ("continuous", "fenestrated" or "discontinuous") and functional properties (e.g permeability, expression of surface molecules, responses to hemodynamic forces, pacemaker cells). For example, there are marked structural and functional differences between the endothelial lining of the lung and the brain. In the pulmonary endothelium, the level of adhesion molecule expression is constitutively high, allowing to maintain a large pool of marginated leukocytes. Endothelial cells in the brain are characterized by the lack of fenestrations and an elaborate system of tight junctions limiting and controlling exchange with the interstitial compartment. A central component of endothelial function in many organs is the release of active substances in response to chemical agonists and to hemodynamic forces, including NO, prostacyclin and EDHF (endothelium derived hyperpolarizing factor). These substances control vascular tone, but also structural vascular adaptation, proliferation, and inflammation. In recent years, it became increasingly clear that the luminal endothelial surface is covered with a gel-like layer exhibiting a thickness in the range of 0.5 to 1 mm. This layer has been named endothelial surface layer (ESL) and is much thicker as compared to the so called glycocalyx which consists of proteoglycanes and glycoproteins anchored in the endothelial
plasma membrane (typical thickness of about 50-100mm). While the composition of the ESL still remains largely elusive, adsorbed plasma proteins and hyaluronan seem to be essential. Due to its wide ranging roles for fluid exchange, flow resistance, oxygen transport, vascular control, coagulation, inflammation, and atherosclerosis, the ESL will be a relevant focus for future studies in endothelial function. E-mail address: [email protected]
2 Effects of shear stress on endothelial activation and vascular inflammation Paul C. Evans BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, UK Atherosclerosis is a chronic lipid-driven inflammatory disease of arteries that causes heart attack or stroke. Early lesions (fatty streaks) contain monocytes and T lymphocytes which are recruited from the circulation to activated vascular endothelial cells (EC) which express adhesion molecules (e.g. Eselectin, VCAM-1) and chemokines (e.g. IL-8, MCP-1) at their surface. This process relies on dual activation of NFkB and MAP kinase e AP-1 signaling pathways which leads to transcriptional activation of pro-inflammatory genes. Hemodynamics play a central role in regulating vascular inflammation and atherosclerosis which occurs predominantly at branches and bends of the arterial tree that are exposed to relatively low or re-circulating blood flow. In contrast, regions of the arterial tree with uniform geometry that are exposed to high rates of unidirectional flow are protected from inflammation and atherosclerosis. Blood flow exerts shear stress (mechanical drag) at the interface between blood and the endothelial layer, where it induces a shearing deformation of the endothelial cells. Thus protected regions of the arterial tree with uniform geometry are exposed to high
Abstracts / Biomedicine & Pharmacotherapy 62 (2008) 503e512
504
shear stress, whereas susceptible regions, e.g. arches and branches, are exposed to low / oscillatory shear. Shear stress regulates vascular inflammation and atherosclerosis by altering the physiology of endothelial cells (EC), which detect shear stress via a tri-molecular complex expressed at their surface. High shear stress suppresses EC activation by inhibiting pro-inflammatory NF-kB and MAP kinase e AP-1 signaling via mechanisms that involve the activation of KLF2 and Nrf2 transcription factors. In contrast, low and oscillatory shear enhances endothelial activation via activation of MAP kinase e AP-1 and NF-kB pathways. These mechanisms are likely to contribute to the focal distribution of atherosclerotic lesions and could potentially be exploited to design novel therapeutic strategies to protect susceptible regions of the arterial tree from inflammation and atherosclerosis. E-mail address: [email protected]
3 Leukocyte-Endothelial Interactions with Respect to the Adhesion Cascade Dr Victoria Ridger Cardiovascular Research Unit, School of Medicine and Biomedical Sciences,University of Sheffield, UK Leukocyte recruitment to the site of injury and inflammation occurs via a sequence highly regulated events, collectively known as the adhesion cascade. They are characterised as capture, rolling, slow rolling, crawling, adhesion and extravasation. At each step, leukocytes interact with the endothelium through adhesion molecules; the selectins and their ligands regulate the first contact events and rolling whereas the integrins are involved in the later stages. Not only do these molecules control the physical interactions between leukocytes and endothelial cells, but they also are involved in signalling and preparing the leukocyte for the subsequent steps in the cascade. The onset of inflammation increases the expression and alters the avidity of these adhesion molecules on both the leukocytes and the endothelium, increasing the adhesive environment. Marginated leukocytes make initial contact with endothelial cells through interaction of L- (on leukocyte) or P- (on endothelial cells) selectins with their respective ligands. Rolling then occurs through a series of bond formations at the leading edge and breakages at the trailing edge of the leukocyte. The next stage of the cascade is slow rolling, mediated by E-selectin, observed after longer periods of endothelial stimulation. Slow rolling is thought to play a role in prolonging the exposure of rolling leukocytes to chemokines. Rolling also triggers cell signalling events thought to prepare the cell for the next step of ‘‘firm’’ adhesion. Chemokines are involved in the transition of rolling into firm adhesion and in the shedding of L-selectin from the surface of leukocytes. Firm adhesion is known to be highly dependent on b2 integrins and their ligands, members of the immunoglobulin superfamily. Once firmly adherent, leukocytes crawl towards endothelial-endothelial cell junctions via these same interactions. Transendothelial migration is
generally thought to occur in an intercellular manner and is mediated by integrin PECAM-1, ICAM-2, JAM-A and CD99. However this latter stage is not as well characterised. The understanding of the adhesion cascade and the multiple steps involved in leukocyte recruitment is essential for the development of effective, novel therapies for inflammatory diseases. E-mail address: [email protected]
4 Vascular device interaction with the endothelium Mark Atherton 1, Ashraf W Khir 1, Marco Cavazzuti 2, Giovanni Barozzi 2, & Michael Collins 1 1
School of Engineering and Design, Brunel University, West London, UK 2 Dipartminto di Ingegneria Meccanica e Civile, Universita` di Modena e Reggio Emilia, Italy Cerebral stents and Intra Aortic Balloon Pumps (IABP) are examples of mechanical devices that are inserted into arteries to restore flows to clinically healthy states. The stent and the IABP ‘correct’ the arterial flow by static dilation and by cyclical occlusion respectively. As this presentation shows, these functions are effectively modelled by current engineering practice. As interventions however, by their very nature they involve physical contact between a non-biological structure and the sensitive endothelial surface. The possible damage to the endothelium is not currently well addressed and we also consider this issue. Cerebral stents generally have two primary clinical objectives: to mechanically dilate a stenosed artery and to have minimal detrimental impact upon local blood flow characteristics. These objectives are well served at the arterial scale as these devices are evidently effective in opening up diseased arteries and restoring vital flows. However, at the near-wall micro-scale the picture is less satisfactory, as thin stent wires apply stresses to the endothelium and glycocalyx and the local flow is disturbed rather than being ideally streamlined. This causes further interaction with this endothelium topography. Wall Shear Stress (WSS) is the measure commonly used to indicate the interaction between fluid and wall but it is a broad brush approach that loses fidelity close to the wall. We will present simulation results of blood flow through a stented cerebral saccular aneurysm under these limitations of WSS. The Intra Aortic Balloon Pump (IABP) is a widely used temporary cardiac assist device. The balloon is usually inserted from the iliac artery, advanced in the aorta until it reaches the desired position; with its base just above the renal bifurcation and the tip approximately 10cm away from the aortic valve. The balloon is inflated and deflated every(1:1), every other- (1:2) or every second (1:3) cardiac cycle. Balloon inflation, which takes place during early diastole, causes an increase in the pressure of the aortic root which leads to an increase in coronary flow. Balloon deflation which