Biorheology - Volume 46, issue 4

Authors: Dong, C. | Robertson, G.P.

Article Type: Research Article

Abstract: Attachment of tumor cells to the endothelium (EC) under flow conditions is critical for migration of tumor cells out of the vascular system to establish metastases. We found that neutrophils (PMN) increased melanoma cell extravasation. Endogenous IL-8 liberated from melanoma cells or from PMN induced by melanoma cells contributed to PMN-facilitated melanoma cell arrest on the EC in the microcirculation. Functional blocking of IL-8 receptors on PMN or neutralizing soluble IL-8 in the tumor circulation decreased the level of CD11b/CD18 up-regulation on PMN and subsequently reduced melanoma cell extravasation. We also found that targeting mutant V600E B-Raf interrupted melanoma cell …extravasation in vitro and subsequent lung metastasis development in vivo. B-Raf encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Results showed that inhibition of V600E B-Raf reduced IL-8 secretion from melanoma cells and reduced the capacity of IL-8 production from the tumor microenvironment involving PMN. Furthermore, reduction in intercellular adhesion molecule-1 (ICAM-1) expression on melanoma cells was found after V600E B-Raf knockdown. These results provide new evidence for the complex role of secreted chemokine and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the EC, which are significant in fostering new approaches to cancer treatment through anti-inflammatory therapeutics. Show more

Keywords: PMN, melanoma, endothelium, shear flow, cytokine signaling, extravasation

DOI: 10.3233/BIR-2009-0545

Citation: Biorheology, vol. 46, no. 4, pp. 265-279, 2009

Authors: Marhefka, J.N. | Zhao, R. | Wu, Z.J. | Velankar, S.S. | Antaki, J.F. | Kameneva, M.V.

Article Type: Research Article

Abstract: This paper reports a novel, physiologically significant, microfluidic phenomenon generated by nanomolar concentrations of drag-reducing polymers (DRP) dissolved in flowing blood, which may explain previously demonstrated beneficial effects of DRP on tissue perfusion. In microfluidic systems used in this study, DRP additives were found to significantly modify traffic of red blood cells (RBC) into microchannel branches as well as reduce the near-wall cell-free layer, which normally is found in microvessels with a diameter smaller than 0.3 mm. The reduction in plasma layer size led to attenuation of the so-called “plasma skimming” effect at microchannel bifurcations, increasing the number of RBC …entering branches. In vivo, these changes in RBC traffic may facilitate gas transport by increasing the near vessel wall concentration of RBC and capillary hematocrit. In addition, an increase in near-wall viscosity due to the redirection of RBC in this region may potentially decrease vascular resistance as a result of increased wall shear stress, which promotes endothelium mediated vasodilation. These microcirculatory phenomena can explain the previously reported beneficial effects of DRP on hemodynamics in vivo observed in many animal studies. We also report here our finding that DRP additives reduce flow separations at microchannel expansions, deflecting RBC closer to the wall and eliminating the plasma recirculation zone. Although the exact mechanism of the DRP effects on RBC traffic in microchannels is yet to be elucidated, these findings may further DRP progress toward clinical use. Show more

Keywords: Blood soluble drag-reducing polymers, microcirculation, wall shear stress, “plasma skimming” effect, flow separations, RBC traffic

DOI: 10.3233/BIR-2009-0543

Citation: Biorheology, vol. 46, no. 4, pp. 281-292, 2009

Authors: Pacella, John J. | Kameneva, Marina V. | Lavery, Linda L. | Bowry, Shivani | Schwartz, Abigail | Fischer, Andrew | Villanueva, Flordeliza S.

Article Type: Research Article

Abstract: We have shown that drag-reducing polymers (DRP) restore perfusion to a stenotic bed by lowering microvascular resistance. We studied whether resistance-lowering by DRP are due to changes in hydrodynamics or vasodilation. During intravital microscopy of rat cremaster muscle (n=18), DRP infusion increased aortic flow (p<0.002), decreased vascular resistance (p<0.01), increased arteriolar diameter (p=0.023), and increased RBC velocity in the arterioles (p<0.04), venules (p<0.003) and capillaries (p<0.02). To investigate whether DRP lowers resistance without involvement of shear (nitric oxide [NO])-mediated vasodilation, L-NAME was infused in 19 rats, but failed to abolish DRP resistance-lowering. To further investigate whether DRP resistance-lowering depends on …vasodilation, adenosine was infused into rabbit femoral arteries (n=19) prior to DRP to achieve marked vasodilation. DRP caused an additional 14% decrease in femoral vascular resistance (p=0.022). DRP enhance microcirculatory perfusion by lowering vascular resistance. This involves not only some degree of shear-induced vasodilation, but also tone-independent resistance lowering mechanisms, suggesting that DRP favorably alter blood flow hydrodynamics. Modulation of blood flow hydrodynamics to enhance perfusion is unique, and may be of therapeutic value for any condition of compromised blood flow. Show more

Keywords: Vasodilation, coronary arterioles, coronary microvessels, microcirculation, drag reducing polymers

DOI: 10.3233/BIR-2009-0547

Citation: Biorheology, vol. 46, no. 4, pp. 293-308, 2009

Authors: Li, Yixuan | Vanapalli, Siva A. | Duits, Michel H.G.

Article Type: Research Article

Abstract: We studied the dynamics of ballistically injected latex particles (BIP) inside endothelial cells, using video particle tracking to measure the mean squared displacement (MSD) as a function of lag time. The MSD shows a plateau at short times and a linear behavior at longer times, indicating that the BIP are trapped into a viscoelastic network. To reveal more about the molecular constituents and the dynamics of this actin network, we added a variety of drugs. Latrunculin and Jasplakinolide aimed at intervening with the actin network caused a strong increase in MSD, whereas Taxol aimed at microtubules gave no measurable change …in MSD. Additional corroborating information about these drug effects were obtained from MSD amplitude and exponent distributions and from fluorescent staining images of the actin and microtubule networks. Our evidence strongly suggests that BIP are primarily embedded in the actin network. Additional drug interventions aimed at disabling non-thermal forces could not conclusively resolve the nature of the forces driving BIP dynamics. Show more

Keywords: Endothelial cells, actin cytoskeleton, viscoelasticity, ballistic injection, particle tracking

DOI: 10.3233/BIR-2009-0542

Citation: Biorheology, vol. 46, no. 4, pp. 309-321, 2009

Authors: Calderon, Andres J. | Muzykantov, Vladimir | Muro, Silvia | Eckmann, David M.

Article Type: Research Article

Abstract: Vascular drug delivery by administration of carriers targeted to endothelial surface determinants, such as intercellular adhesion molecule (ICAM-1), holds considerable promise to improve disease treatment. As a model to define elusive factors controlling the interplay between carrier motion in the bloodstream and its interactions with molecular targets in the endothelial wall, we used 1 μm beads coated with ICAM-1 monoclonal antibody (Ab) at 370, 1100 or 4100 Ab/μm2 . Carriers were perfused at two shear rates over resting or activated endothelial cells, expressing minimum vs. maximum ICAM-1 levels, to determine carrier rolling, binding and detachment. Even at 0.1 Pa and …4100 Ab/μm2 , carriers attached only to activated cells (21 fold increase over resting cells), ideal for specific drug targeting to sites of pathology. Binding was increased by raising the Ab surface density on the carrier, e.g., 59.4±11.1% increase for carriers having 4100 vs. 1100 Ab/μm2 , as a consequence of decreased rolling velocity. Carrier binding was stable even under a high shear stress: carriers with 1100 and 4100 Ab/μm2 withstand shear stress over 3 Pa without detaching from the cells. This is further supported by theoretical modeling. These results will guide vascular targeting of drug carriers via rational design of experimentally tunable parameters. Show more

Keywords: Drug delivery, endothelium, ICAM targeting, particles, targeted delivery

DOI: 10.3233/BIR-2009-0544

Citation: Biorheology, vol. 46, no. 4, pp. 323-341, 2009

Authors: Yu, François T.H. | Franceschini, Émilie | Chayer, Boris | Armstrong, Jonathan K. | Meiselman, Herbert J. | Cloutier, Guy

Article Type: Research Article

Abstract: Ultrasound characterization of erythrocyte aggregation (EA) is attractive because it is a non-invasive imaging modality that can be applied in vivo and in situ. An experimental validation of the Structure Factor Size Estimator (SFSE), a non-Rayleigh scattering model adapted for dense suspensions, was performed on 4 erythrocyte preparations with different aggregation tendencies. Erythrocyte preparations were circulated in Couette and tube flows while acoustically imaged over a bandwidth of 9–28 MHz. Two acoustically derived parameters, the packing factor (W) and ensemble averaged aggregate size (D), predictably increased with increasing EA, a finding corroborated by bulk viscosity measurements. In tube flow, a …“black hole” reflecting the absence of aggregates was observed in the center stream of some parametric images. The SFSE clearly allowed quantifying the EA spatial distribution with larger aggregates closer to the tube walls as the aggregation tendency was increased. In Couette flow, W and D were uniformly distributed across the shear field. Assuming that the viscosity increase at low shear is mainly determined by EA, viscosity maps were computed in tube flow. Interestingly, erythrocyte suspensions with high aggregabilities resulted in homogeneous viscosity distributions, whereas a “normal” aggregability promoted the formation of concentric rings with varying viscosities. Show more

Keywords: Ultrasound backscattering coefficient, ultrasound tissue characterization, packing factor, Born approximation, non-Rayleigh scattering, hemorheology, local viscosity

DOI: 10.3233/BIR-2009-0546

Citation: Biorheology, vol. 46, no. 4, pp. 343-363, 2009