Blood Flow Shear Stress Research Articles

The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostatis and pathophysiology

It is widely accepted that vascular mechanisms are involved in the genesis of many neurological disorders. In particular, blood–brain barrier (BBB) dysfunction has been related to the severity of Alzheimer's disease, encephalopathy due to meningitis, multiple sclerosis, HIV-associated encephalopathy, epilepsy, gliomas and metastatic brain tumors. The BBB may constitute an important therapeutic target to protect neurons after CNS diseases. Both in vivo and in vitro, the functional phenotype of vascular endothelium is dynamically responsive to circulating cytokines, growth factors and puslatile blood flow (shear stress). Shear stress can play a critical role in vascular homeostasis and pathophysiology; it is a major regulator of remodeling in developed blood vessels and in blood vessels affected by atherosclerotic lesions. The physiological fluid mechanic stimulus, shear stress, could be considered to be an important 'differentiative' stimulus capable of modulating endothelial phenotype in vivo. Endothelial cells undergo cell cycle arrest after exposure to physiological levels of shear stress. As for mature endothelial cells, in which flow mediated shear stress may play a role in the induction, progression and/or prevention of atherosclerosis by changing their function, stress may play a role in endothelial cell differentiation from hemopoietic stem cells and/or from embryonic stem cells. Stem cells may be used to repair vascular damage, including loss of EC, due to a variety of diseases (e.g. myocardial neovascularization by adult bone marrow derived angioblasts). In the brain, it was proposed that neuron-producing stem cells may be used to treat Alzheimer's disease, paralysis, etc. Surprisingly, very few investigators are exploring the use of endothelial precursors to revert or prevent cerebrovascular disease. This review summarizes the most recent data related to cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in blood–brain barrier homeostasis and pathophysiology.

Myocardial bridging is associated with alteration in coronary vasoreactivity

Shear stress alteration has been recognized as a predisposing factor for the impairment of endothelial function. Myocardial bridging is a congenital condition associated with alteration in shear stress, however, its impact upon vasoreactivity remains undetermined. This was a case-control designed study with 29 patients with myocardial bridging and 58 patients without myocardial bridging. Endothelium-dependent and endothelium-independent changes in coronary artery diameters, blood flow and wall shear stress were determined after intracoronary infusion of acetylcholine (ACH, 10(-6)-10(-4) mol/L) and nitroglycerine (NTG, 200 microg). Coronary flow velocity reserve (CFVR) was determined after intracoronary injection of adenosine (18-36 microg). In response to ACH, there was more epicardial vasoconstriction at the myocardial bridging site compared with the proximal and distal segments (-29.6+/-21.7 vs. -9.6+/-22.5 and -17.4+/-21.5%, p<0.05) and compared with the control group (-29.6+/-21.7 vs. -5.9+/-36.5%, p<0.001). The response to NTG and CFVR was the same in the case and the control group. Wall shear rate (WSR) was higher in the MB site at baseline and in response to ACH. MB is characterised by enhanced WSR and impairment in endothelium-dependent vasorelaxation. These functional alterations may add to the severity of structural lumen compression and thus to the clinical presentation of this congenital abnormality.

Hemodynamic forces regulate mural macrophage infiltration in experimental aortic aneurysms

Blood flow (BF) and wall shear stress (WSS) influence reactive oxygen species production and oxidative stress in abdominal aortic aneurysm (AAA) disease. To gain further insight into the mechanisms of hemodynamic influences on AAA inflammation, we examined aneurysm macrophage density, chemotaxis and survival under varying aortic flow conditions. Rat AAAs were created via porcine pancreatic elastase (PPE) infusion. In selected cohorts, AAA flow was increased via left common femoral arteriovenous fistula (AVF) creation (HF-AAA) or decreased by left common iliac ligation (LF-AAA). WSS was highest in HF-AAA (10.4 ± 2.3 dyn/cm 2 vs. 2.4 ± 0.4 and 0.5 ± 0.2 for NF- and LF-AAA, respectively, P < 0.001) 7 days after PPE infusion, with reduced medial macrophage density and increased apoptosis. Adventitial macrophage density was not significantly influenced by flow. Monocyte chemoattractant protein-1 (MCP-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression correlated with observed macrophage densities in the media and adventitia. Luminal flow conditions regulate AAA inflammation in part via influences on medial macrophage density. Hemodynamic forces may modulate AAA inflammation and diameter enlargement via direct regulation of intimal macrophage adhesion, transmural migration or survival.

Effects of pulsatile shear stress on nitric oxide production and endothelial cell nitric oxide synthase expression by ovine fetoplacental artery endothelial cells.

Placental blood flow, endothelial nitric oxide (NO) production, and endothelial cell nitric oxide synthase (eNOS) expression increase during pregnancy. Shear stress, the frictional force exerted on endothelial cells by blood flow, stimulates vessel dilation, endothelial NO production, and eNOS expression. In order to study the effects of pulsatile flow/shear stress, we adapted Cellco CELLMAX artificial capillary modules to study ovine fetoplacental artery endothelial (OFPAE) cells for NO production and eNOS expression. OFPAE cells were grown in the artificial capillary modules at 3 dynes/cm2. Confluent cells were then exposed to 10, 15, or 25 dynes/cm2 for up to 24 h. NO production by OFPAE cells exposed to pulsatile shear stress was inhibited to nondetectable levels by the NOS inhibitor l-NMMA and reversed by excess NOS substrate l-arginine. NO production and expression of eNOS mRNA and protein by OFPAE cells were elevated by shear stress in a graded fashion (P < 0.05). The rise in NO production with 25 dynes/cm2 shear stress (8-fold) was greater (P < 0.05) than that observed for eNOS protein (3.6-fold) or eNOS mRNA (1.5-fold). The acute shear stress-induced rise in NO production by OFPAE cells was via eNOS activation, whereas the prolonged NO rise occurred by elevations in both eNOS expression and enzyme activation. Thus, elevations of placental blood flow and physiologic shear stress may be partly responsible for the increases in placental arterial endothelial eNOS expression and NO production during pregnancy.

Stress and vascular responses: atheroprotective effect of laminar fluid shear stress in endothelial cells: possible role of mitogen-activated protein kinases.

Atherosclerosis preferentially occurs in areas of turbulent blood flow and low fluid shear stress, whereas laminar blood flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent findings suggest a steady laminar blood flow decreases EC apoptosis and inhibits TNF-mediated EC activation. EC apoptosis or activation is suggested to be involved in plaque erosion, which may lead to platelet aggregation. TNF-alpha regulates gene expression in ECs, in part, by stimulating mitogen-activated protein (MAP) kinases, which phosphorylate transcription factors. We hypothesized that steady laminar flow inhibits cytokine-mediated activation of MAP kinases in ECs. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm(2)) on TNF-alpha-stimulated activity of three MAP kinases in human umbilical vein ECs (HUVEC): extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. TNF-alpha activated ERK1/2, JNK, and p38 maximally at 15 min in HUVEC. Pre-exposing HUVEC for 10 min to flow inhibited TNF-alpha activation of JNK, but showed no significant effect on ERK1/2 or p38 activation. Incubation of HUVEC with PD98059, a specific ERK1/2 inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Transfection studies with dominant-negative constructs of the protein kinase MEK5 suggested an important role for big mitogen-activated protein kinase 1 (BMK1) in flow-mediated regulation of EC activation by TNF-alpha. Understanding the mechanisms by which steady laminar flow regulates JNK activation by cytokines may provide insight into the atheroprotective mechanisms induced by laminar blood flow.

Laminar Flow Induction of Antioxidant Response Element-mediated Genes in Endothelial Cells: A NOVEL ANTI-INFLAMMATORY MECHANISM

Atherosclerotic lesions preferentially develop in areas of the vasculature exposed to nonlaminar blood flow and low fluid shear stress, whereas laminar flow and high fluid shear stress are athero-protective. We have identified a set of genes including NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), ferritin (heavy and light chains), microsomal epoxide hydrolase, glutathione S-transferase, and gamma-glutamylcysteine synthase, whose expression is induced by exposure to prolonged physiological levels of steady laminar flow (shear stress = 20 dyn/cm(2)) in endothelial cells (EC). These genes contain an antioxidant response element (ARE) or ARE-like transcriptional regulatory sequence in their promoters and generally function to protect cells against oxidant stress. We demonstrate that exposure of EC to laminar flow activates ARE-mediated transcriptional activity. Mutation of the ARE from either the NQO1 or HO-1 promoter abolished laminar flow-induced NQO1 and HO-1 transcriptional activation. Expression of antisense Nrf2 (a transcriptional factor for ARE), a dominant negative Nrf2, or the cytoplasmic inhibitor of Nrf2 (Keap1/INrf2) inhibited laminar flow-induced NQO1 promoter activation in EC. In addition, expression of NQO1 or Nrf2 inhibited tumor necrosis factor-alpha-induced activation of VCAM-1 (vascular cell adhesion molecule-1) gene expression in EC. These data define the ARE as a novel endothelial shear stress response element. Furthermore, laminar flow activation of antioxidant genes via an ARE-dependent transcriptional mechanism may represent a novel athero-protective and anti-inflammatory mechanism in the vasculature.

Intracellular calcium changes in rat aortic smooth muscle cells in response to fluid flow.

Vascular smooth muscle cells (VSM) are normally exposed to transmural fluid flow shear stresses, and after vascular injury, blood flow shear stresses are imposed upon them. Since Ca2+ is a ubiquitous intracellular signaling molecule, we examined the effects of fluid flow on intracellular Ca2+ concentration in rat aortic smooth muscle cells to assess VSM responsiveness to shear stress. Cells loaded with fura 2 were exposed to steady flow shear stress levels of 0.5-10.0 dyn/cm2 in a parallel-plate flow chamber. The percentage of cells displaying a rise in cytosolic Ca2+ ion concentration ([Ca2+]i) increased in response to increasing flow, but there was no effect of flow on the ([Ca2+]i) amplitude of responding cells. Addition of Gd3+ (10 microM) or thapsigargin (50 nM) significantly reduced the percentage of cells responding and the response amplitude, suggesting that influx of Ca2+ through ion channels and release from intracellular stores contribute to the rise in ([Ca2+]i) in response to flow. The addition of nifedipine (1 or 10 microM) or ryanodine (10 microM) also significantly reduced the response amplitude, further defining the role of ion channels and intracellular stores in the Ca2+ response.

Remodeling and suppression of intimal hyperplasia of vascular grafts with a distal arteriovenous fistula in a rat model

Purpose: The purpose of this study was to evaluate the effects of a distal arteriovenous fistula (dAVF) on the morphologic changes occurring in arterial bypass grafts by the use of a novel experimental model. Methods: Aortofemoral bypass grafts with or without dAVFs were constructed in 36 Sprague-Dawley rats with a microsurgical technique. The bypass graft material consisted of deendothelialized autogenous tail artery (length, 25 mm; inside diameter, 0.5 mm). In 18 rats, dAVFs were constructed at the distal anastomosis. After 6 weeks, flow rates and shear stress were determined, and grafts were then harvested. Luminal, intimal, and medial cross-sectional areas were measured with computer imaging. Desmin, α–smooth muscle actin, and von Willebrand factor (vWF) were identified with immunohistochemistry. Endothelialization was evaluated with SEM. Results: All bypass grafts remained patent at the time of graft harvest. Grafts with dAVFs showed increased flow rates (11.5 ± 0.6 mL/min) compared with grafts without dAVFs (2.1 ± 0.3 mL/min; P <.01). Shear stress was also increased in the dAVF group (340.9 ± 23.4 dyne/cm2 vs 113.7 ± 12.5 dyne/cm2; P <.01), with a corresponding suppression of intimal hyperplasia (0.059 ± 0.011 mm2 for dAVF grafts vs 0.225 ± 0.009 mm2 for non-dAVF grafts; P <.01). Staining for vWF was found in both the reendothelialized flow surface and the neointimal extracellular matrix. Remodeling of the grafts was characterized by a 50% increased luminal area, 70% decreased intimal area, and a 25% decreased medial area when a dAVF was constructed. Conclusion: A small animal experimental model of an arterial bypass graft can enable the evaluation of a variety of factors that influence graft patency. Increased blood flow velocity and shear stress induced by a dAVF are associated with a decrease in intimal and medial areas, which may reflect changes in cell proliferation, apoptosis, migration, or matrix deposition. Deposition of vWF was also found both in the endothelium and throughout the hyperplastic intima. These findings suggest that the hemodynamic and morphologic changes associated with dAVF may potentiate graft patency and function. (J Vasc Surg 2001;34:701-6.)

Characteristics of arterial wall shear stress which cause endothelium-dependent vasodilatation in the anaesthetized dog.

1. The effects of changes in the mean and amplitude of arterial wall shear stress on endothelium-dependent arterial dilatation of the iliac artery of the anaesthetized dog were examined. 2. Changes in the mean and amplitude of blood flow and wall shear stress were brought about by varying local peripheral resistance and stroke volume using a distal infusion of acetylcholine and the stimulation of the left ansa subclavia. Changes in the diameter of a segment of the iliac artery with the endothelium intact, relative to a segment with no endothelium, were used as an index of the release of nitric oxide. 3. The increase in mean blood flow was from 84 +/- 12 to 527 +/- 53 ml min-1 and in amplitude was from 365 +/- 18 to 695 +/- 38 ml min-1 (means +/- S.E.M.). The increase in mean wall shear stress was from 1.78 +/- 0.30 to 7.66 +/- 1.01 N m-2 and in amplitude was from 7.37 +/- 0.46 to 13.9 +/- 2.00 N m-2 (means +/- S.E.M.). 4. Increases in mean shear stress caused an increase in the diameter only of the section of artery with endothelium; the slope of the relationship was 0.064 +/- 0.006 mm N-1 m2 (mean +/- S.E.M., P < 0.001); changes in the amplitude of shear stress did not cause an increase in diameter. Changes in both the mean and amplitude of shear stress had no significant effect on the diameter of the section of artery with no endothelium. 5. These findings coupled with the known anti-atheroma effects of nitric oxide and the effect of shear stress on cell adhesion and platelet aggregation offer a possible explanation for the disposition of atheroma in those parts of the arterial system which have low mean and high amplitude of wall shear stress.

Intravascular hemodynamic factors responsible for progression of coronary atherosclerosis and development of vulnerable plaque.

The initiation, localization, growth, composition, and rupture of intracoronary atheromatous plaque-factors that define the natural history of coronary artery disease-are all dependent on inhomogenieties and irregularities of intracoronary local blood flow and endothelial shear stress. Restenosis of mechanically recanalized coronary arteries may be related in part to similar abnormalities of disturbed local flood flow and shear stress. Low or reversed shear stress leads to plaque development and progression. High shear stress contributes significantly to plaque rupture. Regions of hemodynamic stasis caused by major luminal irregularities may lead to thrombosis and myocardial infarction without plaque rupture. This review outlines the mechanisms that link hemodynamic factors to plaque development and rupture and describes in some detail recently developed techniques that, for the first time, make it possible to determine these factors in vivo in patients during routine cardiac catheterization procedures.

Mechanisms for regulation of fluid shear stress response in circulating leukocytes.

We have shown that leukocytes retract their pseudopods and detach from substrates after exposure to physiological fluid shear stresses ( approximately 1.5 dyn/cm(2)). In inflammation, however, pseudopod projection during spreading and firm adhesion on endothelium is observed even in microvessels with normal blood flow and fluid shear stresses. Thus, we examined mechanisms that may serve to regulate the shear stress response of circulating leukocytes. In the presence of inflammatory mediators (platelet-activating factor [PAF] f-met-leu-phe), a subgroup of cells ceases to respond to shear stress. cGMP analogs and nitric oxide (NO) donors enhance the shear stress response and reverse the inhibitory effect of inflammatory mediators on the shear stress response, whereas depletion of cGMP leads to cessation of the shear stress response even in unstimulated leukocytes. The ability of cGMP to enhance the shear stress response is not associated with CD18 expression, because cGMP has no effect on CD18 expression in response to shear stress. The shear stress response of leukocytes in endothelial nitric oxide synthase (-/-) mice, in which NO level in blood is decreased, is attenuated compared with that in wild-type mice. In rat mesentery venules stimulated by PAF under normal blood flow, a cGMP analog diminishes pseudopod projection of leukocytes, whereas inhibition of NO leads to enhanced pseudopod projection and spreading. The evidence suggests that inflammatory mediators suppress the shear stress response of leukocytes leading to spreading even under normal physiological shear stress, whereas cGMP may serve to maintain shear stress response even in inflammation.

The effects of external compression on venous blood flow and tissue deformation in the lower leg.

External pneumatic compression of the lower legs is effective as prophylaxis against deep vein thrombosis. In a typical application, inflatable cuffs are wrapped around the patient's legs and periodically inflated to prevent stasis, accelerate venous blood flow, and enhance fibrinolysis. The purpose of this study was to examine the stress distribution within the tissues, and the corresponding venous blood flow and intravascular shear stress with different external compression modalities. A two-dimensional finite element analysis (FEA) was used to determine venous collapse as a function of internal (venous) pressure and the magnitude and spatial distribution of external (surface) pressure. Using the one-dimensional equations governing flow in a collapsible tube and the relations for venous collapse from the FEA, blood flow resulting from external compression was simulated. Tests were conducted to compare circumferentially symmetric (C) and asymmetric (A) compression and to examine distributions of pressure along the limb. Results show that A compression produces greater vessel collapse and generates larger blood flow velocities and shear stresses than C compression. The differences between axially uniform and graded-sequential compression are less marked than previously found, with uniform compression providing slightly greater peak flow velocities and shear stresses. The major advantage of graded-sequential compression is found at midcalf. Strains at the lumenal border are approximately 20 percent at an external pressure of 50 mmHg (6650 Pa) with all compression modalities.

Numerical simulation of pulsatile flow in a compliant curved tube model of a coronary artery.

The endothelial cells (ECs) lining a blood vessel wall are exposed to both the wall shear stress (WSS) of blood flow and the circumferential strain (CS) of pulsing artery wall motion. These two forces and their interaction are believed to play a role in determining remodeling of the vessel wall and development of arterial disease (atherosclerosis). This study focused on the WSS and CS dynamic behavior in a compliant model of a coronary artery taking into account the curvature of the bending artery and physiological radial wall motion. A three-dimensional finite element model with transient flow and moving boundaries was set up to simulate pulsatile flow with physiological pressure and flow wave forms characteristic of the coronary arteries. The characteristic coronary artery curvature and flow conditions applied to the simulation were: aspect ratio (lambda) = 10, diameter variation (DV) = 6 percent, mean Reynolds number (Re) = 150, and unsteadiness parameter (alpha) = 3. The results show that mean WSS is about 50 percent lower on the inside wall than the outside wall while WSS oscillation is stronger on the inside wall. The stress phase angle (SPA) between CS and WSS, which characterizes the dynamics of the mechanical force pattern applied to the endothelial cell layer, shows that CS and WSS are more out of phase in the coronaries than in any other region of the circulation (-220 deg on the outside wall, -250 deg on the inside wall). This suggests that in addition to WSS, SPA may play a role in localization of coronary atherosclerosis.

Alterations in pulmonary artery flow patterns and shear stress determined with three-dimensional phase-contrast magnetic resonance imaging in fontan patients

Objective: This study compares in vivo pulmonary blood flow patterns and shear stresses in patients with either the direct atrium–pulmonary artery connection or the bicaval tunnel connection of the Fontan procedure to those in normal volunteers. Comparisons were made with the use of three-dimensional phase contrast magnetic resonance imaging. Methods: Three-dimensional velocities, flows, and pulmonary artery cross-sectional areas were measured in both pulmonary arteries of each subject. Axial, circumferential, and radial shear stresses were calculated with the use of velocities and estimates of viscosity. Results: The axial velocities were not significantly different between subject groups. However, the flows and cross-sectional areas were higher in the normal group than in the two patient groups in both pulmonary arteries. The group with the bicaval connection had circular swirling in the cross section of both pulmonary arteries, causing higher shear stresses than in the controls. The disorder caused by the connection of the atrium to the pulmonary artery caused an increase in some shear stresses over the controls, but not higher than those found in the group having a bicaval tunnel. Conclusions: We found that pulmonary flow was equally reduced compared with normal flow in both patient groups. This reduction in flow can be attributed in part to the reduced size of the pulmonary arteries in both patient groups without change in axial velocity. We also found higher shear stress acting on the wall of the vessels in the patients having a bicaval tunnel, which may alter endothelial function and affect the longevity of the repair. (J Thorac Cardiovasc Surg 1998;116:294-304)

Flow waveform effects on end-to-side anastomotic flow patterns

Purpose: Restenosis due to distal anastomotic intimal hyperplasia, a leading cause of arterial bypass graft failure, is thought to be promoted by hemodynamic effects, specifically ‘abnormal’ wall shear stress patterns. The purpose of this study was to quantify the effects of flow waveform on peri-anastomotic flow and wall shear stress patterns. Methods: Blood flow and wall shear stress patterns were numerically computed in a representative three-dimensional anastomosis using femoral, iliac and coronary flow waveforms suitable for humans at rest. Numerical results were validated against experimental data. Results: Peri-anastomotic wall shear stress patterns were influenced by a complex interplay between secondary flow effects and unsteadiness. Peripheral flow waveforms (iliac, femoral) produced large temporal and spatial wall shear stress gradients on the host artery bed. In comparison, the coronary flow waveform produced normalized bed wall shear stress gradients that were a factor of 2–3 less than for the peripheral waveforms, even though average bed wall shear stress magnitudes were similar for the two waveforms. Conclusions: If anastomotic intimal hyperplasia is promoted by large spatial and/or temporal gradients of wall shear stress, as has been proposed, this study predicts that there will be markedly less intimal hyperplasia on the host artery bed of coronary bypass grafts than for peripheral bypass grafts. This information, in conjunction with a comparative histopathologic study of intimal hyperplasia distribution, could help determine specific wall shear stress factors promoting intimal hyperplasia.

Static and dynamic lengths of neutrophil microvilli.

Containing most of the L-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) on their tips, microvilli are believed to promote the initial arrest of neutrophils on endothelium. At the rolling stage following arrest, the lifetimes of the involved molecular bonds depend on the pulling force imposed by the shear stress of blood flow. With two different methods, electron microscopy and micropipette manipulation, we have obtained two comparable neutrophil microvillus lengths, both approximately 0.3 microm in average. We have found also that, under a pulling force, a microvillus can be extended (microvillus extension) or a long thin membrane cylinder (a tether) can be formed from it (tether formation). If the force is </=34 pN (+/- 3 pN), the length of the microvillus will be extended; if the force is >61 pN (+/- 5 pN), a tether will be formed from the microvillus at a constant velocity, which depends linearly on the force. When the force is between 34 pN and 61 pN (transition zone), the degree of association between membrane and cytoskeleton in individual microvilli will dictate whether microvillus extension or tether formation occurs. When a microvillus is extended, it acts like a spring with a spring constant of approximately 43 pN/microm. In contrast to a rigid or nonextendible microvillus, both microvillus extension and tether formation can decrease the pulling force imposed on the adhesive bonds, and thus prolonging the persistence of the bonds at high physiological shear stresses.

Plasma von Willebrand Factor in Patients with Acute Myocardial Infarction

Acute myocardial infarction is known to be caused by thrombotic occlusion of coronary arteries. Although several investigators have suggested the abnormalities of plasma hemostatic parameters in patients with myocardial infarction, the relationship between these events and the onset of coronary thrombosis is still unclear. Recent in vitro investigations suggest the importance of the interaction between plasma ligand protein, von Willebrand factor (vWF), and platelet glycoproteins in the onset of arterial thrombosis, which occurs under the high shear stress of blood flow. In the present study, we investigated hemostatic abnormalities in patients with acute myocardial infarction by measuring plasma indicators including thrombin antithrombin III complex (TAT), plasminogen activator inhibitor 1 (PAI-1), the antigen level and ristocetin cofactor activities of vWF, and multimer analysis of vWF. In addition to hypercoagulabilities and increased antithrombolytic activities, a significant increase in antigen level or ristocetin cofactor activity of vWF was observed in patients with acute myocardial infarction. Although further study is needed, the increased levels of vWF in acute myocardial infarction may contribute to the re-occlusion of coronary artery after reperfusion treatment.

Expression of Endothelin-1 and Constitutional Nitric Oxide Synthase Messenger RNA in Saphenous Vein Endothelial Cells Exposed to Arterial Flow Shear Stress

It has long been speculated that increased blood flow shear stress might be one of the major factors affecting the patency of grafted saphenous vein in coronary artery bypass operations. The underlying cellular and molecular mechanisms for so-called "shear stress damage" have not yet been well elucidated. Endothelial cells harvested from human saphenous vein were cultured in vitro and then exposed to a high arterial level flow shear stress in the parallel flow chamber. The expression levels of endothelin-1 and constitutional nitric oxide synthase by the endothelial cells were evaluated semiquantitatively at the gene transcription (messenger RNA) level using reverse transcription polymerase chain reaction. After 7 hours of exposure to arterial level shear stress, the expression of constitutional nitric oxide synthase messenger RNA by saphenous vein endothelial cells was significantly reduced, whereas the expression of endothelin-1 messenger RNA was substantially increased. These changes were more predominant at 24 hours. Arterial level flow shear stress could cause important changes in the gene transcription level in saphenous vein endothelial cells within a short period of time. The functional alterations of saphenous vein endothelial cells, as manifested by the increased expression of endothelin-1 and decreased expression of nitric oxide synthase messenger RNA, might play a crucial role in the vein graft remodeling process.

A lumped parameter model to evaluate the fluid dynamics of different coronary bypasses

Coronary bypass grafting is a surgical procedure frequently performed to obtain myocardial reperfusion downstream from severe coronary stenoses. Different surgical techniques may be adopted which include the use of graft made of internal mammary artery or saphenous vein, and the adoption of multiple or sequential bypasses for more than one stenosis. The haemodynamics of the surgically reconstructed coronary bed is strongly dependent on the bypass configuration and may induce atherogenic processes affecting the long-term potency of the bypass. We have improved a closed-loop mathematical model of the cardiovascular system including a more detailed description of the coronary tree which allows the calculation of the flow rate and pressure curves in all the vessels considered. Pathological situations, such as stenoses, have been simulated and investigated. Models of the internal mammary artery and of the saphenous vein have also been developed in order to simulate coronary artery bypasses. The four simulated bypass configurations have been the single saphenous vein, the sequential saphenous vein, the single internal mammary artery and the sequential internal mammary artery. Results of the simulations of the different bypass grafting configurations indicate that between single saphenous vein and single internal mammary artery the latter shows better haemodynamics both for the flow rate pattern and for the calculated wall shear stress. The sequential bypasses show better haemodynamics in comparison with the single bypass in the proximal segments and worse performance in the distal ones. The models may be applied as an investigative tool to evaluate actual cases of surgically treatable coronary stenoses. They can predict the modification in blood flow waveforms, mean velocities, shear stress and distribution of blood flow in the coronary branches as a function of the adopted bypass configuration.

Acute reductions in blood flow and shear stress induce platelet-derived growth factor-A expression in baboon prosthetic grafts.

Abrupt reductions in fluid shear stress induce subendothelial smooth muscle cells (SMCs) to proliferate in experimental prosthetic grafts. Platelet-derived growth factor (PDGF), an important SMC mitogen, is expressed by cultured endothelial cells and modulated by shear stress. We hypothesized that this growth factor would be modulated by changes in shear stress in vivo. Bilateral aortoiliac prosthetic grafts were implanted into five baboons. High flow was generated by construction of femoral arteriovenous fistulas on both sides. Two months later, one of the fistulas was ligated, reducing shear stress in the upstream graft by 78 +/- 6%. Four days after fistula ligation, all grafts were removed and analyzed. As previously reported, SMC proliferation in low-flow grafts exceeded that in high-flow grafts, although the neointimal area was similar. mRNA levels for PDGF-A were significantly increased in low-flow grafts compared with high-flow grafts. In situ hybridization and immunohistochemical studies localized the increased PDGF-A mRNA and protein to the luminal endothelium and subjacent SMCs. Abrupt reductions in blood flow and fluid shear stress may induce accelerated neointimal thickening by a PDGF-A-mediated mechanism, since endothelial expression of this gene is temporally and anatomically associated with neointimal SMC proliferation.