Effects of flow geometry on blood viscoelasticity

The viscoelastic properties of blood are dominated by microstructures formed by red cells. The microstructures are of several types such as irregular aggregates, rouleaux, and layers of aligned cells. The dynamic deformability of the red cells, aggregation tendency, cell concentration, size of confining vessel and rate of flow are determining factors in the microstructure. Viscoelastic properties, viscosity and elasticity, relate to energy loss and storage in flowing blood while relaxation time and Weissenberg number play a role in assessing the importance of the elasticity relative to the viscosity. These effects are shown herein for flow in a large straight cylindrical tube, a small tube, and a porous medium. These cases approximate the geometries of the arterial system: large vessels, small vessels and vessels with many branches and bifurcations. In each case the viscosity, elasticity, relaxation time and Weissenberg number for normal human blood as well as blood with enhanced cell aggregation tendency and diminished cell deformability are given. In the smaller spaces of the microtubes and porous media, the diminished viscosity shows the possible influence of the F?hraeus-Lindqvist effect and at high shear rates, the viscoelasticity of blood shows dilatancy. This is true for normal, aggregation enhanced and hardened cells.     

Non-Newtonian effects of blood flow on hemodynamics in distal vascular graft anastomoses

Non-Newtonian fluid flow in a stenosed coronary bypass is investigated numerically using the Carreau-Yasuda model for the shear thinning behavior of the blood. End-to-side coronary bypass anastomosis is considered in a simplified model geometry where the host coronary artery has a 75% severity stenosis. Different locations of the bypass graft to the stenosis and different flow rates in the graft and in the host artery are studied. Particular attention is given to the non-Newtonian effect of the blood on the primary and secondary flow patterns in the host coronary artery and the wall shear stress (WSS) distribution there. Interaction between the jet flow from the stenosed artery and the flow from the graft is simulated by solving the three-dimensional Navier-Stokes equation coupled with the non-Newtonian constitutive model. Results for the non-Newtonian flow, the Newtonian flow and the rescaled Newtonian flow are presented. Significant differences in axial velocity profiles, secondary flow streamlines and WSS between the non-Newtonian and Newtonian fluid flows are revealed. However, reasonable agreement between the non-Newtonian and the rescaled Newtonian flows is found. Results from this study support the view that the residual flow in a partially occluded coronary artery interacts with flow in the bypass graft and may have significant hemodynamic effects in the host vessel downstream of the graft. Non-Newtonian property of the blood alters the flow pattern and WSS distribution and is an important factor to be considered in simulating hemodynamic effects of blood flow in arterial bypass grafts.     

Muscle oxygenation and ATP turnover when blood flow is impaired by vascular disease

³¹P magnetic resonance spectroscopy (³¹P MRS) and near-infrared spectroscopy (NIRS) are combined to study interactions between oxidative ATP synthesis rate, perturbation of the creatine kinase equilibrium, and cellular oxygenation state in calf muscle of normal subjects and patients with muscle perfusion impaired by peripheral vascular disease.     

Shear stress and intravascular pressure effects on vascular dynamics: two-phase blood flow in elastic microvessels accounting for the passive stresses

Biomechanics and Modeling in Mechanobiology - We study the steady hemodynamics in physiological elastic microvessels proposing an advanced fluid–structure interaction model. The arteriolar...     

Gossypol effects on endothelial cells and tumor blood flow

Isomers (-, +) of the antitumor agent gossypol (G) were studied for their ability to reduce tumor ATP and blood flow in rats bearing subcutaneously implanted pancreatic tumors. A 50% reduction in tumor ATP/Pi within ih of a single injection of -G was associated with a 60% decline in tumor blood flow. To determine if these changes in tumor physiology could be due to a direct drug effect on tumor endothelium, G isomers were compared for their ability to alter protein (125I-BSA) permeability and metabolic (32P) labelling of cultured endothelial cells. Treatments for ih produced no endothelial cell leakage, but 24h exposures to either -G (5 microM) or +G (50 microM) produced complete permeability of the monolayers to 125I-BSA. In contrast, 0.5-I.Oh exposures to -G (4 microM) produced 2 to 3-fold increases in phosphorylated 27 kDa heat-shock protein, hsp-27. Hsp-27 phosphoprotein isoforms were differentially labelled following -G and +G exposures with the phosphorylation profile of -G appearing most similar to that of oxyradical producing agents known to induce hsp-27 and injure endothelial cells. We postulate that the tumor ischemic effects of -G are mediated by endothelial response to oxyradical production in a mechanism similar to that of tissue ischemia-reperfusion injury.     

Melatonin differentially affects vascular blood flow in humans

Melatonin is synthesized and released into the circulation by the pineal gland in a circadian rhythm. Melatonin has been demonstrated to differentially alter blood flow to assorted vascular beds by the activation of different melatonin receptors in animal models. The purpose of the present study was to determine the effect of melatonin on blood flow to various vascular beds in humans. Renal (Doppler ultrasound), forearm (venous occlusion plethysmography), and cerebral blood flow (transcranial Doppler), arterial blood pressure, and heart rate were measured in 10 healthy subjects (29±1 yr; 5 men and 5 women) in the supine position for 3 min. The protocol began 45 min after the ingestion of either melatonin (3 mg) or placebo (sucrose). Subjects returned at least 2 days later at the same time of day to repeat the trial after ingesting the other substance. Melatonin did not alter heart rate and mean arterial pressure. Renal blood flow velocity (RBFV) and renal vascular conductance (RVC) were lower during the melatonin trial compared with placebo (RBFV, 40.5±2.9 vs. 45.4±1.5 cm/s; and RVC, 0.47±0.02 vs. 0.54±0.01 cm·s(-1)·mmHg(-1), respectively). In contrast, forearm blood flow (FBF) and forearm vascular conductance (FVC) were greater with melatonin compared with placebo (FBF, 2.4±0.2 vs. 1.9±0.1 ml·100 ml(-1)·min(-1); and FVC, 0.029±0.003 vs. 0.023±0.002 arbitrary units, respectively). Melatonin did not alter cerebral blood flow measurements compared with placebo. Additionally, phentolamine (5-mg bolus) after melatonin reversed the decrease in RVC, suggesting that melatonin increases sympathetic outflow to the kidney to mediate renal vasoconstriction. In summary, exogenous melatonin differentially alters vascular blood flow in humans. These data suggest the complex nature of melatonin on the vasculature in humans.     

Tyrosine phosphatase inhibition augments collateral blood flow in a rat model of peripheral vascular disease

During embryonic development, the growth of blood vessels requires the coordinated activation of endothelial receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptor-2 (VEGFR-2) and Tie-2. Similarly, in adulthood, activation of endothelial RTKs has been shown to enhance development of the collateral circulation and improve blood flow to ischemic tissues. Recent evidence suggests that RTK activation is negatively regulated by protein tyrosine phosphatases (PTPs). In this study, we used the nonselective PTP inhibitor bis(maltolato)oxovanadium IV (BMOV) to test the potential efficacy of PTP inhibition as a means to enhance endothelial RTK activation and improve collateral blood flow. In cultured endothelial cells, pretreatment with BMOV augmented VEGFR-2 and Tie-2 tyrosine phosphorylation and enhanced VEGF- and angiopoietin-1-mediated cell survival. In rat aortic ring explants, BMOV enhanced vessel sprouting, a process that can be influenced by both VEGFR-2 and Tie-2 activation. Moreover, 2 wk of BMOV treatment in a rat model of peripheral vascular disease enhanced collateral blood flow similarly to VEGF, and after 4 wk, BMOV was superior to VEGF. Taken together, these studies provide evidence that PTPs are important regulators of endothelial RTK activation and for the first time demonstrate the potential utility of phosphatase inhibition as a means to promote collateral development and enhance collateral blood flow to ischemic tissue.     

The initiation of blood flow and flow induced events in early vascular development

Within a day of gastrulation, the embryonic heart begins to beat and creates blood flow in the developing cardiovascular system. The onset of blood flow completely changes the environment in which the cardiovascular system is forming. Flow provides physiological feedback such that the developing network adapts to cue provided by the flow. Targeted inactivation of genes that alter early blood fluid dynamics induce secondary defects in the heart and vasculature and therefore proper blood flow is known to be essential for vascular development. Though hemodynamics, or blood fluid dynamics, are known to activate signaling pathways in the mature cardiovascular system in pathologies ranging from artherosclerosis to angiogenesis, the role in development has not been as intensively studied. The question arises how blood vessels in the embryos, which initially lack cells types such as smooth muscle cells, differ in their response to mechanical signals from blood flow as compared to the more mature cardiovascular system. Many genes known to be regulated by hemodynamics in the adult are important for developmental angiogenesis. Therefore the onset of blood flow is of primary importance to vascular development. This review will focus on how blood flow initiates and the effects of the mechanical signals created by blood flow on cardiovascular development.     

Analysis of venous flow transients for estimation of vascular resistance, compliance, and blood flow distribution

We analysed venous flow transients using a long venous circuit and right heart bypass in 17 dogs after a rapid decrease in atrial pressure. A biphase curve was obtained which we decomposed into a two-compartment model, one with a fast time constant for venous return (0.069 min) and 52% of total circulating flow (Q), and one with a slower time constant (0.456 min) and 48% of Q. Subsequently, separate drainage from splanchnic and peripheral beds (with the renal venous return in the peripheral bed drainage) allowed comparison of time constants and venous outflow in these beds. The sum of the venous outflow volumes over time during separate drainage was indistinguishable from the single biphasic venous outflow volume curve over time observed with a long circuit and single reservoir. The fast time constant of the biphasic curve was not different from that determined by separate drainage from the peripheral circulation. The slow time constant of the single biphasic curve of 0.456 min was hybrid of two time constants, 0.216 min in the splanchnic bed and 0.862 min in the peripheral bed. Separate drainage from peripheral and splanchnic vascular beds demonstrated that the peripheral bed constituted 70% of venous outflow in the fast time constant compartment using Caldini's technique, whereas the splanchnic bed constituted 63% of venous outflow in the slow time constant compartment. It is concluded that, although Caldini's technique demonstrates biphasic venous flow transients, neither the fast nor the slow time constant compartments resolved from this analysis represent a particular anatomical region or vascular bed.     

The effects of aging and activity on muscle blood flow

Background

Our purpose was to determine if aging had an influence on muscle blood flow independent of habitual physical activity levels.

Methods

Blood flow was measured in the femoral artery by Doppler ultrasound after cuff occlusion of 10 minutes. Active and inactive older subjects (73 ± 7 years) were compared to active and inactive young subjects (26 ± 6 years).

Results

Peak blood flow capacity when normalized to lean muscle mass was related to activity level (p < 0.001), but not to age. Specifically, the young active group had higher peak blood flows than the young inactive (p = 0.031) or older inactive (p = 0.005) groups. Resting blood flow and conductance were not significantly different between groups. Mean arterial pressure was significantly higher in the older compared to young group (p = 0.002). Conductance was related to both activity (p = 0.002) and age (p = 0.003). A prolonged time for blood flow to recover was found in the older compared to the young group (p = 0.038) independent of activity status.

Conclusions

The prolonged recovery time in the older subjects may suggest a reduced vascular reactivity associated with increased cardiovascular disease risk. Peak blood flow capacity is maintained in older subjects by physical activity. In summary, maximal flow capacity and prolonged recovery of blood flow are influenced by different mechanisms in young and older active and inactive subjects.

     

Novel platforms for vascular carriers with controlled geometry

The first-generation platforms for vascular drug delivery adopted spherical morphologies. These carriers relied primarily on the size dependence of the enhanced permeability and retention effect to passively target vasculature, resulting in inefficient delivery due to significant variation in endothelial permeability. Enhanced delivery typically requires active targeting via receptor-mediated endocytosis by surface conjugation of targeting ligands. However, vascular carriers (VCs) still face numerous challenges en route to reaching their targets before delivery. The control of carrier shape offers opportunities to overcome in vivo barriers and enhance vascular drug delivery. Geometric features influence the ability of carrier particles to navigate physiological flow patterns, evade biological clearance mechanisms, sustain circulation, adhere to the vascular surface, and finally transport across or internalize into the endothelium. Although previous formulation strategies limited the fabrication of nonspherical carriers, numerous recent advances in both top-down and bottom-up fabrication techniques have enabled shape modulation as a key design element. As part of a series on vascular drug delivery, this review focuses on recent developments in novel vascular platforms with controlled geometry that enhance or modulate delivery functions. Starting with an overview of controlled geometry platforms, we review their shape-dependent functional characteristics for each stage of their vascular journey in vivo. We sequentially explore carrier geometries that evade reticuloendothelial system uptake, display enhanced circulation persistence and margination dynamics in flow, encourage adhesion to the vascular surface or extravasation through endothelium, and impact extravascular transport and cell internalization. The eventual biodistribution of VCs results from the culmination of their successive navigation of all these barriers and is profoundly influenced by their morphology. To enhance delivery efficacy, carrier designs synergistically combining controlled geometry with standard drug delivery strategies such as targeting moieties, surface decorations, and bulk material properties are discussed. Finally, we speculate on possibilities for innovation, harnessing shape as a design parameter for the next generation of vascular drug delivery platforms.     

Effect of mesenteric vascular congestion on reflex control of renal blood flow

Portal hypertension initiates a splenorenal reflex, whereby increases in splenic afferent nerve activity and renal sympathetic nerve activity cause a decrease in renal blood flow (RBF). We postulated that mesenteric vascular congestion similarly compromises renal function through an intestinal-renal reflex. The portal vein was partially occluded in anesthetized rats, either rostral or caudal to the junction with the splenic vein. Portal venous pressure increased (6.5 +/- 0.1 to 13.2 +/- 0.1 mmHg; n = 78) and mesenteric venous outflow was equally obstructed in both cases. However, only rostral occlusion increased splenic venous pressure. Rostral occlusion caused a fall in RBF (-1.2 +/- 0.2 ml/min; n = 9) that was attenuated by renal denervation (-0.5 +/- 0.1 ml/min; n = 6), splenic denervation (-0.2 +/- 0.1 ml/min; n = 11), celiac ganglionectomy (-0.3 +/- 0.1 ml/min; n = 9), and splenectomy (-0.5 +/- 0.1 ml/min; n = 6). Caudal occlusion induced a significantly smaller fall in RBF (-0.5 +/- 0.1 ml/min; n = 9), which was not influenced by renal denervation (-0.2 +/- 0.2 ml/min; n = 6), splenic denervation (-0.1 +/- 0.1 ml/min; n = 7), celiac ganglionectomy (-0.1 +/- 0.3 ml/min; n = 8), or splenectomy (-0.3 +/- 0.1 ml/min; n = 7). Renal arterial conductance fell only in intact animals subjected to rostral occlusion (-0.007 +/- 0.002 ml.min(-1).mmHg(-1)). This was accompanied by increases in splenic afferent nerve activity (15.0 +/- 3.5 to 32.6 +/- 6.2 spikes/s; n = 7) and renal efferent nerve activity (32.7 +/- 5.2 to 39.3 +/- 6.0 spikes/s; n = 10). In animals subjected to caudal occlusion, there were no such changes in renal arterial conductance or splenic afferent/renal sympathetic nerve activity. We conclude that the portal hypertension-induced fall in RBF is initiated by increased splenic, but not mesenteric, venous pressure, i.e., we did not find evidence for intestinal-renal reflex control of the kidneys.